Journal articles: 'C-terminal loop'

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MONLEÓN, Daniel, Vicent ESTEVE, Helena KOVACS, Juan J. CALVETE, and Bernardo CELDA. "Conformation and concerted dynamics of the integrin-binding site and the C-terminal region of echistatin revealed by homonuclear NMR." Biochemical Journal 387, no. 1 (March 22, 2005): 57–66. http://dx.doi.org/10.1042/bj20041343.

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Echistatin is a potent antagonist of the integrins αvβ3, α5β1 and αIIbβ3. Its full inhibitory activity depends on an RGD (Arg-Gly-Asp) motif expressed at the tip of the integrin-binding loop and on its C-terminal tail. Previous NMR structures of echistatin showed a poorly defined integrin-recognition sequence and an incomplete C-terminal tail, which left the molecular basis of the functional synergy between the RGD loop and the C-terminal region unresolved. We report a high-resolution structure of echistatin and an analysis of its internal motions by off-resonance ROESY (rotating-frame Overhauser enhancement spectroscopy). The full-length C-terminal polypeptide is visible as a β-hairpin running parallel to the RGD loop and exposing at the tip residues Pro43, His44 and Lys45. The side chains of the amino acids of the RGD motif have well-defined conformations. The integrin-binding loop displays an overall movement with maximal amplitude of 30°. Internal angular motions in the 100–300 ps timescale indicate increased flexibility for the backbone atoms at the base of the integrin-recognition loop. In addition, backbone atoms of the amino acids Ala23 (flanking the R24GD26 tripeptide) and Asp26 of the integrin-binding motif showed increased angular mobility, suggesting the existence of major and minor hinge effects at the base and the tip, respectively, of the RGD loop. A strong network of NOEs (nuclear Overhauser effects) between residues of the RGD loop and the C-terminal tail indicate concerted motions between these two functional regions. A full-length echistatin–αvβ3 docking model suggests that echistatin's C-terminal amino acids may contact αv-subunit residues and provides new insights to delineate structure–function correlations.

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Harouaka, Djamila, and Gail W. Wertz. "Mutations in the C-Terminal Loop of the Nucleocapsid Protein Affect Vesicular Stomatitis Virus RNA Replication and Transcription Differentially." Journal of Virology 83, no. 22 (September 2, 2009): 11429–39. http://dx.doi.org/10.1128/jvi.00813-09.

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ABSTRACT The 2.9-Å structure of the vesicular stomatitis virus nucleocapsid (N) protein bound to RNA shows the RNA to be tightly sequestered between the two lobes of the N protein. Domain movement of the lobes of the N protein has been postulated to facilitate polymerase access to the RNA template. We investigated the roles of individual amino acid residues in the C-terminal loop, involved in long-range interactions between N protein monomers, in forming functional ribonucleoprotein (RNP) templates. The effects of specific N protein mutations on its expression, interaction with the phosphoprotein, and formation of RNP templates that supported viral RNA replication and transcription were examined. Mutations introduced into the C-terminal loop, predicted to break contact with other residues in the loop, caused up to 10-fold increases in RNA replication without an equivalent stimulation of transcription. Mutation F348A, predicted to break contact between the C-terminal loop and the N-terminal arm, formed templates that supported wild-type levels of RNA replication but almost no transcription. These data show that mutations in the C-terminal loop of the N protein can disparately affect RNA replication and transcription, indicating that the N protein plays a role in modulating RNP template function beyond its structural role in RNA encapsidation.

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Burkhart, Michael D., Paul D'Agostino, Samuel C. Kayman, and Abraham Pinter. "Involvement of the C-Terminal Disulfide-Bonded Loop of Murine Leukemia Virus SU Protein in a Postbinding Step Critical for Viral Entry." Journal of Virology 79, no. 12 (June 15, 2005): 7868–76. http://dx.doi.org/10.1128/jvi.79.12.7868-7876.2005.

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ABSTRACT A role for the C-terminal domain (CTD) of murine leukemia virus (MuLV) Env protein in viral fusion was indicated by the potent inhibition of MuLV-induced fusion, but not receptor binding, by two rat monoclonal antibodies (MAbs) specific for epitopes in the CTD. Although these two MAbs, 35/56 and 83A25, have very different patterns of reactivity with viral isolates, determinants of both epitopes were mapped to the last C-terminal disulfide-bonded loop of SU (loop 10), and residues in this loop responsible for the different specificities of these MAbs were identified. Both MAbs reacted with a minor fraction of a truncated SU fragment terminating four residues after loop 10, indicating that while the deleted C-terminal residues were not part of these epitopes, they promoted their formation. Neither MAb recognized the loop 10 region expressed in isolated form, suggesting that these epitopes were not completely localized within loop 10 but required additional sequences located N terminal to the loop. Direct support for a role for loop 10 in fusion was provided by the demonstration that Env mutants containing an extra serine or threonine residue between the second and third positions of the loop were highly attenuated for infectivity and defective in fusion assays, despite wild-type levels of expression, processing, and receptor binding. Other mutations at positions 1 to 3 of loop 10 inhibited processing of the gPr80 precursor protein or led to increased shedding of SU, suggesting that loop 10 also affects Env folding and the stability of the interaction between SU and TM.

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Qiao, Renping, Florian Weissmann, Masaya Yamaguchi, Nicholas G. Brown, Ryan VanderLinden, Richard Imre, Marc A. Jarvis, et al. "Mechanism of APC/CCDC20 activation by mitotic phosphorylation." Proceedings of the National Academy of Sciences 113, no. 19 (April 25, 2016): E2570—E2578. http://dx.doi.org/10.1073/pnas.1604929113.

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Chromosome segregation and mitotic exit are initiated by the 1.2-MDa ubiquitin ligase APC/C (anaphase-promoting complex/cyclosome) and its coactivator CDC20 (cell division cycle 20). To avoid chromosome missegregation, APC/CCDC20 activation is tightly controlled. CDC20 only associates with APC/C in mitosis when APC/C has become phosphorylated and is further inhibited by a mitotic checkpoint complex until all chromosomes are bioriented on the spindle. APC/C contains 14 different types of subunits, most of which are phosphorylated in mitosis on multiple sites. However, it is unknown which of these phospho-sites enable APC/CCDC20 activation and by which mechanism. Here we have identified 68 evolutionarily conserved mitotic phospho-sites on human APC/C bound to CDC20 and have used the biGBac technique to generate 47 APC/C mutants in which either all 68 sites or subsets of them were replaced by nonphosphorylatable or phospho-mimicking residues. The characterization of these complexes in substrate ubiquitination and degradation assays indicates that phosphorylation of an N-terminal loop region in APC1 is sufficient for binding and activation of APC/C by CDC20. Deletion of the N-terminal APC1 loop enables APC/CCDC20 activation in the absence of mitotic phosphorylation or phospho-mimicking mutations. These results indicate that binding of CDC20 to APC/C is normally prevented by an autoinhibitory loop in APC1 and that its mitotic phosphorylation relieves this inhibition. The predicted location of the N-terminal APC1 loop implies that this loop controls interactions between the N-terminal domain of CDC20 and APC1 and APC8. These results reveal how APC/C phosphorylation enables CDC20 to bind and activate the APC/C in mitosis.

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Takemoto, D. J., L. J. Takemoto, J. Hansen, and D. Morrison. "Regulation of retinal transducin by C-terminal peptides of rhodopsin." Biochemical Journal 232, no. 3 (December 15, 1985): 669–72. http://dx.doi.org/10.1042/bj2320669.

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Transducin is a multi-subunit guanine-nucleotide-binding protein that mediates signal coupling between rhodopsin and cyclic GMP phosphodiesterase in retinal rod outer segments. Whereas the T alpha subunit of transducin binds guanine nucleotides and is the activator of the phosphodiesterase, the T beta gamma subunit may function to link physically T alpha with photolysed rhodopsin. In order to determine the binding sites of rhodopsin to transducin, we have synthesized eight peptides (Rhod-1 etc.) that correspond to the C-terminal regions of rhodopsin and to several external and one internal loop region. These peptides were tested for their inhibition of restored GTPase activity of purified transducin reconstituted into depleted rod-outer-segment disc membranes. A marked inhibition of GTPase activity was observed when transducin was pre-incubated with peptides Rhod-1, Rhod-2 and Rhod-3. These peptides correspond to opsin amino acid residues 332-339, 324-331 and 317-321 respectively. Peptides corresponding to the three external loop regions or to the C-terminal residues 341-348 did not inhibit reconsituted GTPase activity. Likewise, Rhod-8, a peptide corresponding to an internal loop region of rhodopsin, did not inhibit GTPase activity. These findings support the concept that these specific regions of the C-terminus of rhodopsin serve as recognition sites for transducin.

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Ren, Chunguang, Satoshi Nagao, Masaru Yamanaka, Hirofumi Komori, Yasuhito Shomura, Yoshiki Higuchi, and Shun Hirota. "Oligomerization enhancement and two domain swapping mode detection for thermostable cytochrome c552via the elongation of the major hinge loop." Molecular BioSystems 11, no. 12 (2015): 3218–21. http://dx.doi.org/10.1039/c5mb00545k.

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High-order oligomers increased whereas N-terminal domain swapping and C-terminal domain swapping were elucidated by the insertion of Gly residues at the major hinge loop of cytochrome c₅₅₂.

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Bury, Loredana, Emanuela Falcinelli, Haripriya Kuchi Bhotla, Anna Maria Mezzasoma, Giuseppe Guglielmini, Alexander Tischer, Laurie Moon-Tasson, Matthew Auton, and Paolo Gresele. "A p.Arg127Gln variant in GPIbα LRR5 allosterically enhances affinity for VWF: a novel form of platelet-type VWD." Blood Advances 6, no. 7 (April 1, 2022): 2236–46. http://dx.doi.org/10.1182/bloodadvances.2021005463.

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Abstract Gain-of-function (GOF) variants in GP1BA cause platelet-type von Willebrand disease (PT-VWD), a rare inherited autosomal dominant bleeding disorder characterized by enhanced platelet GPIbα to von Willebrand factor (VWF) interaction, and thrombocytopenia. To date, only 6 variants causing PT-VWD have been described, 5 in the C-terminal disulfide loop of the VWF-binding domain of GPIbα and 1 in the macroglycopeptide. GOF GP1BA variants generate a high-affinity conformation of the C-terminal disulfide loop with a consequent allosteric conformational change on another region of GPIbα, the leucine-rich-repeat (LRR) domain. We identified a novel GP1BA variant (p.Arg127Gln) affecting the LRR5 domain of GPIbα in a boy with easy bruising and laboratory test results suggestive of PT-VWD. We thus aimed to investigate the impact of the p.Arg127Gln variant on GPIbα affinity for VWF and GPIbα structure. Chinese hamster ovary cells expressing p.Arg127Gln GPIbα showed increased binding of VWF induced by ristocetin and enhanced tethering on immobilized VWF as compared with cells expressing wild-type GPIbα. Surface plasmon resonance confirmed that p.Arg127Gln enhances the binding affinity of GPIbα for VWF. Hydrogen-deuterium exchange mass spectrometry showed that p.Arg127Gln of LRR, while having little effect on the dynamics of the LRR locally, enhances the conformational dynamics of the GPIbα C-terminal disulfide loop structure. Our data demonstrate for the first time that GOF variants outside the GPIbα C-terminal disulfide loop may be pathogenic and that aminoacidic changes in the LRR may cause allosterically conformational changes in the C-terminal disulfide loop of GPIbα, inducing a conformation with high affinity for VWF.

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Uesugi, Y., J. Arima, M. Iwabuchi, and T. Hatanaka. "C-terminal loop of Streptomyces phospholipase D has multiple functional roles." Protein Science 16, no. 2 (December 22, 2006): 197–207. http://dx.doi.org/10.1110/ps.062537907.

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Yano, Yoshiaki, Takuya Shimbo, Yukihiko Sugimoto, and Katsumi Matsuzaki. "Intracellular third loop–C-terminal tail interaction in prostaglandin EP3β receptor." Biochemical and Biophysical Research Communications 371, no. 4 (July 2008): 846–49. http://dx.doi.org/10.1016/j.bbrc.2008.04.180.

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Goch, G., H. Kozłowska, A. Wójtowicz, and A. Bierzyński. "A comparative CD and fluorescence study of a series of model calcium-binding peptides." Acta Biochimica Polonica 46, no. 3 (September 30, 1999): 673–77. http://dx.doi.org/10.18388/abp.1999_4139.

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Lanthanide-saturated peptides analogous to calcium-binding loops of EF-hand proteins can be used to stabilize the alpha-helical structure of peptide or protein segments attached to their C-termini. To study conformational properties of such loop-containing hybrids it is necessary to produce them in bacteria. In peptides obtained in this way the helix will be destabilized by the negatively charged C-terminal alpha-carboxyl groups. We propose to block them by the homoserine lactone. The results presented in this paper indicate that the presence of the lactone even at the C-terminus of the loop does not have any negative effect on the loop helix-nucleation ability. On the other hand, the presence of the alpha-NH3+ at the loop N-terminus leads to a drop of metal-binding constant and loss of the rigid structure of the alpha-helical segment of the loop. The alpha-amino group separated by one glycine residue from the loop N-terminus should also be avoided because it perturbs the conformation of the N-terminal part of the loop and may reduce the loop affinity to lanthanide ions.

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Blodgett, David M., Julie K. De Zutter, Kara B. Levine, Pusha Karim, and Anthony Carruthers. "Structural Basis of GLUT1 Inhibition by Cytoplasmic ATP." Journal of General Physiology 130, no. 2 (July 16, 2007): 157–68. http://dx.doi.org/10.1085/jgp.200709818.

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Cytoplasmic ATP inhibits human erythrocyte glucose transport protein (GLUT1)–mediated glucose transport in human red blood cells by reducing net glucose transport but not exchange glucose transport (Cloherty, E.K., D.L. Diamond, K.S. Heard, and A. Carruthers. 1996. Biochemistry. 35:13231–13239). We investigated the mechanism of ATP regulation of GLUT1 by identifying GLUT1 domains that undergo significant conformational change upon GLUT1–ATP interaction. ATP (but not GTP) protects GLUT1 against tryptic digestion. Immunoblot analysis indicates that ATP protection extends across multiple GLUT1 domains. Peptide-directed antibody binding to full-length GLUT1 is reduced by ATP at two specific locations: exofacial loop 7–8 and the cytoplasmic C terminus. C-terminal antibody binding to wild-type GLUT1 expressed in HEK cells is inhibited by ATP but binding of the same antibody to a GLUT1–GLUT4 chimera in which loop 6–7 of GLUT1 is substituted with loop 6–7 of GLUT4 is unaffected. ATP reduces GLUT1 lysine covalent modification by sulfo-NHS-LC-biotin by 40%. AMP is without effect on lysine accessibility but antagonizes ATP inhibition of lysine modification. Tandem electrospray ionization mass spectrometry analysis indicates that ATP reduces covalent modification of lysine residues 245, 255, 256, and 477, whereas labeling at lysine residues 225, 229, and 230 is unchanged. Exogenous, intracellular GLUT1 C-terminal peptide mimics ATP modulation of transport whereas C-terminal peptide-directed IgGs inhibit ATP modulation of glucose transport. These findings suggest that transport regulation involves ATP-dependent conformational changes in (or interactions between) the GLUT1 C terminus and the C-terminal half of GLUT1 cytoplasmic loop 6–7.

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Bannister, Roger A., Symeon Papadopoulos, Claudia S. Haarmann, and Kurt G. Beam. "Effects of inserting fluorescent proteins into the α1S II–III loop: insights into excitation–contraction coupling." Journal of General Physiology 134, no. 1 (June 29, 2009): 35–51. http://dx.doi.org/10.1085/jgp.200910241.

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In skeletal muscle, intermolecular communication between the 1,4-dihydropyridine receptor (DHPR) and RYR1 is bidirectional: orthograde coupling (skeletal excitation–contraction coupling) is observed as depolarization-induced Ca2+ release via RYR1, and retrograde coupling is manifested by increased L-type Ca2+ current via DHPR. A critical domain (residues 720–765) of the DHPR α1S II–III loop plays an important but poorly understood role in bidirectional coupling with RYR1. In this study, we examine the consequences of fluorescent protein insertion into different positions within the α1S II–III loop. In four constructs, a cyan fluorescent protein (CFP)–yellow fluorescent protein (YFP) tandem was introduced in place of residues 672–685 (the peptide A region). All four constructs supported efficient bidirectional coupling as determined by the measurement of L-type current and myoplasmic Ca2+ transients. In contrast, insertion of a CFP–YFP tandem within the N-terminal portion of the critical domain (between residues 726 and 727) abolished bidirectional signaling. Bidirectional coupling was partially preserved when only a single YFP was inserted between residues 726 and 727. However, insertion of YFP near the C-terminal boundary of the critical domain (between residues 760 and 761) or in the conserved C-terminal portion of the α1S II–III loop (between residues 785 and 786) eliminated bidirectional coupling. None of the fluorescent protein insertions, even those that interfered with signaling, significantly altered membrane expression or targeting. Thus, bidirectional signaling is ablated by insertions at two different sites in the C-terminal portion of the α1S II–III loop. Significantly, our results indicate that the conserved portion of the α1S II–III loop C terminal to the critical domain plays an important role in bidirectional coupling either by conveying conformational changes to the critical domain from other regions of the DHPR or by serving as a site of interaction with other junctional proteins such as RYR1.

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Shen, Yang, Jing-fei Dong, Gabriel M. Romo, Wendy Arceneaux, Andrea Aprico, Elizabeth E. Gardiner, José A. López, Michael C. Berndt, and Robert K. Andrews. "Functional analysis of the C-terminal flanking sequence of platelet glycoprotein Ibα using canine–human chimeras." Blood 99, no. 1 (January 1, 2002): 145–50. http://dx.doi.org/10.1182/blood.v99.1.145.

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Platelet glycoprotein Ib-IX-V (GPIb-IX-V) mediates adhesion to von Willebrand factor (vWF) in (patho)physiological thrombus formation. vWF binds the N-terminal 282 residues of GPIbα, consisting of an N-terminal flank (His1–Ile35), 7 leucine-rich repeats (Leu36–Ala200), a C-terminal flank (Phe201–Gly268), and a sulfated tyrosine sequence (Asp269–Glu282). By expressing canine–human chimeras of GPIbα on Chinese hamster ovary cells, binding sites for functional anti-GPIbα antibodies to individual domains were previously mapped, and it was shown that leucine-rich repeats 2 to 4 were required for optimal vWF recognition under static or flow conditions. Using novel canine–human chimeras dissecting the C-terminal flank, it is now demonstrated that (1) Phe201-Glu225 contains the epitope for AP1, an anti-GPIbα monoclonal antibody that inhibits both ristocetin- and botrocetin-dependent vWF binding; (2) VM16d, an antibody that preferentially inhibits botrocetin-dependent vWF binding, recognizes the sequence Val226-Gly268, surrounding Cys248, which forms a disulfide-bond with Cys209; (3) vWF binding to chimeric GPIbα is comparable to wild-type in 2 chimeras in which the sixth leucine-rich repeat was of the same species as the first disulfide loop (Phe201-Cys248) of the C-terminal flank, suggesting an interaction between these domains may be important for optimal vWF binding; and (4) replacing the C-terminal flank second disulfide loop (Asp249-Gly268) in human GPIbα with the corresponding canine sequence enhanced vWF binding under static and flow conditions, providing the first evidence for a gain-of-function phenotype associated with the second loop of the C-terminal flank.

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Senda, Toshiya, Miki Senda, Takeru Hayashi, and Masanori Hatakeyama. "Structure and function of the CagA oncoprotein from Helicobacter pylori." Acta Crystallographica Section A Foundations and Advances 70, a1 (August 5, 2014): C839. http://dx.doi.org/10.1107/s2053273314091608.

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CagA is known as a major bacterial virulence determinant from Helicobacter pylori and is critical for gastric cancer. Upon delivery into the gastric epithelial cells, CagA localizes to the inner leaflet of the plasma membrane and promiscuously interacts with host proteins such as PAR1b and SHP2. The CagA-PAR1-SHP2 complex potentiates oncogenic signaling. Biochemical and physicochemical analyses revealed that CagA is comprises a structured N-terminal region (residues 1-876) and an intrinsically disordered C-terminal region (residues 877-1186). To understand the structure and function relationship of CagA, we determined the crystal structure of the N-terminal region (residues 1-876) of CagA [1]. The N-terminal CagA is rich in α-helices and composed of three domains. Domain I (residues 24-221) is linked to domain II (residues 303-644) by a disordered loop with about 80 amino acid residues. Domain II has a basic patch composed of 14 lysine and 2 arginine residues. Biological experiments revealed that the basic patch mediates the CagA-phosphatidylserine interaction to localize the inner face of the plasma membrane. In addition, we found that C-terminal disordered region forms a lariat-like loop by the interaction between NBS (residues 645 - 824) and CBS (residues 998 - 1038) in the disordered C-terminal region. The formation of the lariat-like loop facilitates promiscuous interaction of CagA with target protein such as SHP2.

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Mason, A. B., S. A. Brown, and W. R. Church. "A highly conserved surface loop in the C-terminal domain of ovotransferrin (residues 570-584) is remote from the receptor-binding site." Biochemical Journal 266, no. 2 (March 1, 1990): 393–98. http://dx.doi.org/10.1042/bj2660393.

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A peptide corresponding to a surface loop in the C-terminal domain of chicken ovotransferrin (residues 570-584) was made by solid-phase synthesis and used to immunize rabbits. A 15-amino acid-residue disulphide-linked loop occurs in both domains of all five transferrins for which the sequence is available and lies on the opposite side of the iron-binding site from the interdomain cleft. Polyclonal antibodies to the peptide were specific for non-reduced holo-ovotransferrin and the C-terminal domain, as shown by e.l.i.s.a. and immunoblotting. The antibody did not inhibit binding of ovotransferrin to receptors on chick-embryo reticulocytes but was able to bind ovotransferrin bound to the cellular receptors at 0 degree C. The loop composed of residues 570-584 appears to be remote from the transferrin receptor-binding site.

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Cherry, Amy L., Caitriona A. Dennis, Andrew Baron, Leslie E. Eisele, Pia A. Thommes, and Joachim Jaeger. "Hydrophobic and Charged Residues in the C-Terminal Arm of Hepatitis C Virus RNA-Dependent RNA Polymerase Regulate Initiation and Elongation." Journal of Virology 89, no. 4 (November 26, 2014): 2052–63. http://dx.doi.org/10.1128/jvi.01106-14.

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ABSTRACTThe RNA-dependent RNA polymerase (RdRp) of hepatitis C virus (HCV) is essential for viral genome replication. Crystal structures of the HCV RdRp reveal two C-terminal features, a β-loop and a C-terminal arm, suitably located for involvement in positioning components of the initiation complex. Here we show that these two elements intimately regulate template and nucleotide binding, initiation, and elongation. We constructed a series of β-loop and C-terminal arm mutants, which were used forin vitroanalysis of RdRpde novoinitiation and primer extension activities. All mutants showed a substantial decrease in initiation activities but a marked increase in primer extension activities, indicating an ability to form more stable elongation complexes with long primer-template RNAs. Structural studies of the mutants indicated that these enzyme properties might be attributed to an increased flexibility in the C-terminal features resulting in a more open polymerase cleft, which likely favors the elongation process but hampers the initiation steps. A UTP cocrystal structure of one mutant shows, in contrast to the wild-type protein, several alternate conformations of the substrate, confirming that even subtle changes in the C-terminal arm result in a more loosely organized active site and flexible binding modes of the nucleotide. We used a subgenomic replicon system to assess the effects of the same mutations on viral replication in cells. Even the subtlest mutations either severely impaired or completely abolished the ability of the replicon to replicate, further supporting the concept that the correct positioning of both the β-loop and C-terminal arm plays an essential role during initiation and in HCV replication in general.IMPORTANCEHCV RNA polymerase is a key target for the development of directly acting agents to cure HCV infections, which necessitates a thorough understanding of the functional roles of the various structural features of the RdRp. Here we show that even highly conservative changes, e.g., Tyr→Phe or Asp→Glu, in these seemingly peripheral structural features have profound effects on the initiation and elongation properties of the HCV polymerase.

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TOMOO, Koji, Xu SHEN, Koumei OKABE, Yoshiaki NOZOE, Shoichi FUKUHARA, Shigenobu MORINO, Toshimasa ISHIDA, et al. "Crystal structures of 7-methylguanosine 5′-triphosphate (m7GTP)- and P1-7-methylguanosine-P3-adenosine-5′,5′-triphosphate (m7GpppA)-bound human full-length eukaryotic initiation factor 4E: biological importance of the C-terminal flexible region." Biochemical Journal 362, no. 3 (March 8, 2002): 539–44. http://dx.doi.org/10.1042/bj3620539.

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The crystal structures of the full-length human eukaryotic initiation factor (eIF) 4E complexed with two mRNA cap analogues [7-methylguanosine 5′-triphosphate (m7GTP) and P1-7-methylguanosine-P3-adenosine-5′,5′-triphosphate (m7GpppA)] were determined at 2.0Å resolution (where 1Å = 0.1nm). The flexibility of the C-terminal loop region of eIF4E complexed with m7GTP was significantly reduced when complexed with m7GpppA, suggesting the importance of the second nucleotide in the mRNA cap structure for the biological function of eIF4E, especially the fixation and orientation of the C-terminal loop region, including the eIF4E phosphorylation residue. The present results provide the structural basis for the biological function of both N- and C-terminal mobile regions of eIF4E in translation initiation, especially the regulatory function through the switch-on/off of eIF4E-binding protein—eIF4E phosphorylation.

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J. S. Loureiro, Rui, Diogo Vila-Viçosa, Miguel Machuqueiro, Eugene I. Shakhnovich, and Patrícia F. N. Faísca. "The Early Phase of β2m Aggregation: An Integrative Computational Study Framed on the D76N Mutant and the ΔN6 Variant." Biomolecules 9, no. 8 (August 14, 2019): 366. http://dx.doi.org/10.3390/biom9080366.

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Human β2-microglobulin (b2m) protein is classically associated with dialysis-related amyloidosis (DRA). Recently, the single point mutant D76N was identified as the causative agent of a hereditary systemic amyloidosis affecting visceral organs. To get insight into the early stage of the β2m aggregation mechanism, we used molecular simulations to perform an in depth comparative analysis of the dimerization phase of the D76N mutant and the ΔN6 variant, a cleaved form lacking the first six N-terminal residues, which is a major component of ex vivo amyloid plaques from DRA patients. We also provide first glimpses into the tetramerization phase of D76N at physiological pH. Results from extensive protein–protein docking simulations predict an essential role of the C- and N-terminal regions (both variants), as well as of the BC-loop (ΔN6 variant), DE-loop (both variants) and EF-loop (D76N mutant) in dimerization. The terminal regions are more relevant under acidic conditions while the BC-, DE- and EF-loops gain importance at physiological pH. Our results recapitulate experimental evidence according to which Tyr10 (A-strand), Phe30 and His31 (BC-loop), Trp60 and Phe62 (DE-loop) and Arg97 (C-terminus) act as dimerization hot-spots, and further predict the occurrence of novel residues with the ability to nucleate dimerization, namely Lys-75 (EF-loop) and Trp-95 (C-terminus). We propose that D76N tetramerization is mainly driven by the self-association of dimers via the N-terminus and DE-loop, and identify Arg3 (N-terminus), Tyr10, Phe56 (D-strand) and Trp60 as potential tetramerization hot-spots.

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Sugishima, Masakazu, Kei Wada, Keiichi Fukuyama, and Ken Yamamoto. "Crystal structure of phytochromobilin synthase in complex with biliverdin IXα, a key enzyme in the biosynthesis of phytochrome." Journal of Biological Chemistry 295, no. 3 (December 10, 2019): 771–82. http://dx.doi.org/10.1074/jbc.ra119.011431.

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Phytochromobilin (PΦB) is a red/far-red light sensory pigment in plant phytochrome. PΦB synthase is a ferredoxin-dependent bilin reductase (FDBR) that catalyzes the site-specific reduction of bilins, which are sensory and photosynthesis pigments, and produces PΦB from biliverdin, a heme-derived linear tetrapyrrole pigment. Here, we determined the crystal structure of tomato PΦB synthase in complex with biliverdin at 1.95 Å resolution. The overall structure of tomato PΦB synthase was similar to those of other FDBRs, except for the addition of a long C-terminal loop and short helices. The structure further revealed that the C-terminal loop is part of the biliverdin-binding pocket and that two basic residues in the C-terminal loop form salt bridges with the propionate groups of biliverdin. This suggested that the C-terminal loop is involved in the interaction with ferredoxin and biliverdin. The configuration of biliverdin bound to tomato PΦB synthase differed from that of biliverdin bound to other FDBRs, and its orientation in PΦB synthase was inverted relative to its orientation in the other FDBRs. Structural and enzymatic analyses disclosed that two aspartic acid residues, Asp-123 and Asp-263, form hydrogen bonds with water molecules and are essential for the site-specific A-ring reduction of biliverdin. On the basis of these observations and enzymatic assays with a V121A PΦB synthase variant, we propose the following mechanistic product release mechanism: PΦB synthase-catalyzed stereospecific reduction produces 2(R)-PΦB, which when bound to PΦB synthase collides with the side chain of Val-121, releasing 2(R)-PΦB from the synthase.

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Strzelecka-Gołaszewska, H., M. Mossakowska, A. Woźniak, J. Moraczewska, and H. Nakayama. "Long-range conformational effects of proteolytic removal of the last three residues of actin." Biochemical Journal 307, no. 2 (April 15, 1995): 527–34. http://dx.doi.org/10.1042/bj3070527.

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Truncated derivatives of actin devoid of either the last two (actin-2C) or three residues (actin-3C) were used to study the role of the C-terminal segment in the polymerization of actin. The monomer critical concentration and polymerization rate increased in the order: intact actin < actin-2C < actin-3C. Conversely, the rate of hydrolysis of actin-bound ATP during spontaneous polymerization of Mg-actin decreased in the same order, so that, for actin-3C, the ATP hydrolysis significantly lagged behind the polymer growth. Probing the conformation of the nucleotide site in the monomer form by measuring the rates of the bound nucleotide exchange revealed a similar change upon removal of either the two or three residues from the C-terminus. The C-terminal truncation also resulted in a slight decrease in the rate of subtilisin cleavage of monomeric actin within the DNAse-I binding loop, whereas in F-actin subunits the susceptibility of this and of another site within this loop, specifically cleaved by a proteinase from Escherichia coli A2 strain, gradually increased upon sequential removal of the two and of the third residue from the C-terminus. From these and other observations made in this work it has been concluded that perturbation of the C-terminal structure in monomeric actin is transmitted to the cleft, where nucleotide and bivalent cation are bound, and to the DNAse-I binding loop on the top of subdomain 2. Further changes at these sites, observed on the polymer level, seem to result from elimination of the intersubunit contact between the C-terminal residues and the DNAse-I binding loop. It is suggested that formation of this contact plays an essential role in regulating the hydrolysis of actin-bound ATP associated with the polymerization process.

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Langedijk, Johannes P. M. "Translocation Activity of C-terminal Domain of Pestivirus Ernsand Ribotoxin L3 Loop." Journal of Biological Chemistry 277, no. 7 (October 22, 2001): 5308–14. http://dx.doi.org/10.1074/jbc.m104147200.

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Truong, Amy B., Shane C. Masters, Hongzhu Yang, and Haian Fu. "Role of the 14-3-3 C-terminal loop in ligand interaction." Proteins: Structure, Function, and Bioinformatics 49, no. 3 (November 15, 2002): 321–25. http://dx.doi.org/10.1002/prot.10210.

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23

Koschel, Matthias, Reiner Thomssen, and Volker Bruss. "Extensive Mutagenesis of the Hepatitis B Virus Core Gene and Mapping of Mutations That Allow Capsid Formation." Journal of Virology 73, no. 3 (March 1, 1999): 2153–60. http://dx.doi.org/10.1128/jvi.73.3.2153-2160.1999.

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ABSTRACT We generated a large number of mutations in the hepatitis B virus (HBV) core gene inserted into a bacterial expression vector. The new mutagenesis procedure generated deletions and insertions (as sequence repeats) of various lengths at random positions between M1 and E145 but not substitutions. The R-rich 30-amino-acid C-terminal domain was not analyzed. A total of 50,000 colonies were tested with a polyclonal human serum for the expression of hepatitis B core or e antigen. A total of 110 mutants randomly chosen from 1,500 positive colonies were genotyped. Deletions and insertions were clustered in four regions: D2 to E14, corresponding to the N-terminal loop in a model for the core protein fold (B. Bottcher, S. A. Wynne, and R. A. Crowther, Nature 386:88–91, 1997); V27 to P50 (second loop); L60 to V86 (upper half of the alpha helix forming the N-terminal part of the spike and the tip of the spike); and V124 to L140 (C-terminal part of the C-terminal helix and downstream loop). Deletions or insertions in the remaining parts of the molecule forming the compact center of the fold seemed to destabilize the protein. Of the 110 mutations, 38 allowed capsid formation in Escherichia coli. They mapped exclusively to nonhelical regions of the proposed fold. The mutations form a basis for subsequent analysis of further functions of the HBV core protein in the viral life cycle.

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24

Ostapenko, Denis, and Mark J. Solomon. "Phosphorylation by Cak1 Regulates the C-Terminal Domain Kinase Ctk1 in Saccharomyces cerevisiae." Molecular and Cellular Biology 25, no. 10 (May 15, 2005): 3906–13. http://dx.doi.org/10.1128/mcb.25.10.3906-3913.2005.

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ABSTRACT Ctk1 is a Saccharomyces cerevisiae cyclin-dependent protein kinase (CDK) that assembles with Ctk2 and Ctk3 to form an active protein kinase complex, CTDK-I. CTDK-I phosphorylates Ser2 within the RNA polymerase II C-terminal domain, an activity that is required for efficient transcriptional elongation and 3′ RNA processing. Ctk1 contains a conserved T loop, which undergoes activating phosphorylation in other CDKs. We show that Ctk1 is phosphorylated on Thr-338 within the T loop. Mutation of this residue abolished Ctk1 kinase activity in vitro and resulted in a cold-sensitive phenotype. As with other yeast CDKs undergoing T-loop phosphorylation, Ctk1 phosphorylation on Thr-338 was dependent on the Cak1 protein kinase. Ctk1 isolated from cak1Δ cells was unphosphorylated and exhibited low protein kinase activity. Moreover, Cak1 directly phosphorylated Ctk1 in vitro. Unlike wild-type cells, cells expressing Ctk1T338A delayed growth at early stationary phase, did not show the increase in Ser2 phosphorylation that normally accompanies the transition from rapid growth to stationary phase, and had compromised transcriptional activation of two stationary-phase genes, CTT1 and SPI1. Therefore, Ctk1 phosphorylation on Thr-338 is carried out by Cak1 and is required for normal gene transcription during the transition into stationary phase.

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Lee, Haekyung, Hyukwoo Shin, Eckard Wimmer, and Aniko V. Paul. "cis-Acting RNA Signals in the NS5B C-Terminal Coding Sequence of the Hepatitis C Virus Genome." Journal of Virology 78, no. 20 (October 15, 2004): 10865–77. http://dx.doi.org/10.1128/jvi.78.20.10865-10877.2004.

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ABSTRACT The cis-replicating RNA elements in the 5′ and 3′ nontranslated regions (NTRs) of the hepatitis C virus (HCV) genome have been thoroughly studied before. However, no cis-replicating elements have been identified in the coding sequences of the HCV polyprotein until very recently. The existence of highly conserved and stable stem-loop structures in the RNA polymerase NS5B coding sequence, however, has been previously predicted (A. Tuplin, J. Wood, D. J. Evans, A. H. Patel, and P. Simmonds, RNA 8:824-841, 2002). We have selected for our studies a 249-nt-long RNA segment in the C-terminal NS5B coding region (NS5BCR), which is predicted to form four stable stem-loop structures (SL-IV to SL-VII). By deletion and mutational analyses of the RNA structures, we have determined that two of the stem-loops (SL-V and SL-VI) are essential for replication of the HCV subgenomic replicon in Huh-7 cells. Mutations in the loop and the top of the stem of these RNA elements abolished replicon RNA synthesis but had no effect on translation. In vitro gel shift and filter-binding assays revealed that purified NS5B specifically binds to SL-V. The NS5B-RNA complexes were specifically competed away by unlabeled homologous RNA, to a small extent by 3′ NTR RNA, and only poorly by 5′ NTR RNA. The other two stem-loops (SL-IV and SL-VII) of the NS5BCR domain were found to be important but not essential for colony formation by the subgenomic replicon. The precise function(s) of these cis-acting RNA elements is not known.

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Gul, Mehreen, Ahmad Navid, Muhammad Fakhar, and Sajid Rashid. "SHP-1 tyrosine phosphatase binding to c-Src kinase phosphor-dependent conformations: A comparative structural framework." PLOS ONE 18, no. 1 (January 13, 2023): e0278448. http://dx.doi.org/10.1371/journal.pone.0278448.

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SHP-1 is a cytosolic tyrosine phosphatase that is primarily expressed in hematopoietic cells. It acts as a negative regulator of numerous signaling pathways and controls multiple cellular functions involved in cancer pathogenesis. This study describes the binding preferences of SHP-1 (pY536) to c-Srcopen (pY416) and c-Srcclose (pY527) through in silico approaches. Molecular dynamics simulation analysis revealed more conformational changes in c-Srcclose upon binding to SHP-1, as compared to its active/open conformation that is stabilized by the cooperative binding of the C-SH2 domain and C-terminal tail of SHP-1 to c-Src SH2 and KD. In contrast, c-Srcclose and SHP-1 interaction is mediated by PTP domain-specific WPD-loop (WPDXGXP) and Q-loop (QTXXQYXF) binding to c-Srcclose C-terminal tail residues. The dynamic correlation analysis demonstrated a positive correlation for SHP-1 PTP with KD, SH3, and the C-terminal tail of c-Srcclose. In the case of the c-Srcopen-SHP-1 complex, SH3 and SH2 domains of c-Srcopen were correlated to C-SH2 and the C-terminal tail of SHP-1. Our findings reveal that SHP1-dependent c-Src activation through dephosphorylation relies on the conformational shift in the inhibitory C-terminal tail that may ease the recruitment of the N-SH2 domain to phosphotyrosine residue, resulting in the relieving of the PTP domain. Collectively, this study delineates the intermolecular interaction paradigm and underlying conformational readjustments in SHP-1 due to binding with the c-Src active and inactive state. This study will largely help in devising novel therapeutic strategies for targeting cancer development.

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Epp, Simone F., Thilo Köhler, Patrick Plésiat, Mehri Michéa-Hamzehpour, Joachim Frey, and Jean-Claude Pechère. "C-Terminal Region of Pseudomonas aeruginosa Outer Membrane Porin OprD Modulates Susceptibility to Meropenem." Antimicrobial Agents and Chemotherapy 45, no. 6 (June 1, 2001): 1780–87. http://dx.doi.org/10.1128/aac.45.6.1780-1787.2001.

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ABSTRACT We investigated the unusual susceptibility to meropenem observed for seven imipenem-resistant clinical isolates of Pseudomonas aeruginosa. These strains were genetically closely related, expressed OprD, as determined by Western blot analyses, and were resistant to imipenem (>5 μg/ml) but susceptible to meropenem (<1 μg/ml). The oprD genes from two isolates were entirely sequenced, and their deduced protein sequences showed 93% identity with that of OprD of strain PAO1. The major alteration consisted of the replacement of a stretch of 12 amino acids, located in putative external loop L7 of OprD, by a divergent sequence of 10 amino acid residues. The oprD gene variants and the wild-typeoprD gene were cloned and expressed in a definedoprD mutant. The meropenem MICs for strains carrying theoprD genes from clinical isolates were four times lower than that for the strain carrying the wild-type oprDgene. Imipenem activities, however, were comparable for all strains. Furthermore, meropenem hypersusceptibility was obtained with a hybrid OprD porin that consisted of the PAO1 oprD gene containing loop L7 from a clinical isolate. These results show that the C-terminal portion of OprD, in particular, loop L7, was responsible for the unusual meropenem hypersusceptibility. Competition experiments suggested that the observed OprD modifications in the clinical isolates did not affect antagonism between imipenem and the basic amino acidl-lysine. We further propose that shortening of putative loop L7 of the OprD porin by 2 amino acid residues sufficiently opens the porin channel to allow optimal penetration of meropenem and increase its activity. In contrast, this alteration would not affect susceptibility to a smaller carbapenem molecule, such as imipenem.

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Sanford, J. C., Y. Pan, and M. Wessling-Resnick. "Properties of Rab5 N-terminal domain dictate prenylation of C-terminal cysteines." Molecular Biology of the Cell 6, no. 1 (January 1995): 71–85. http://dx.doi.org/10.1091/mbc.6.1.71.

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Rab5 is a Ras-related GTP-binding protein that is post-translationally modified by prenylation. We report here that an N-terminal domain contained within the first 22 amino acids of Rab5 is critical for efficient geranylgeranylation of the protein's C-terminal cysteines. This domain is immediately upstream from the "phosphate binding loop" common to all GTP-binding proteins and contains a highly conserved sequence recognized among members of the Rab family, referred to here as the YXYLFK motif. A truncation mutant that lacks this domain (Rab5(23-215) fails to become prenylated. However, a chimeric peptide with the conserved motif replacing cognate Rab5 sequence (MAYDYLFKRab5(23-215) does become post-translationally modified, demonstrating that the presence of this simple six amino acid N-terminal element enables prenylation at Rab5's C-terminus. H-Ras/Rab5 chimeras that include the conserved YXYLFK motif at the N-terminus do not become prenylated, indicating that, while this element may be necessary for prenylation of Rab proteins, it alone is not sufficient to confer properties to a heterologous protein to enable substrate recognition by the Rab geranylgeranyl transferase. Deletion analysis and studies of point mutants further reveal that the lysine residue of the YXYLFK motif is an absolute requirement to enable geranylgeranylation of Rab proteins. Functional studies support the idea that this domain is not required for guanine nucleotide binding since prenylation-defective mutants still bind GDP and are protected from protease digestion in the presence of GTP gamma S. We conclude that the mechanism of Rab geranylgeranylation involves key elements of the protein's tertiary structure including a conserved N-terminal amino acid motif (YXYLFK) that incorporates a critical lysine residue.

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Okamoto, Hisayo, Tove Hammarberg, Ying-Yi Zhang, Bengt Persson, Takashi Watanabe, Bengt Samuelsson, and Olof Rådmark. "Mutation analysis of the human 5-lipoxygenase C-terminus: Support for a stabilizing C-terminal loop." Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics 1749, no. 1 (May 2005): 123–31. http://dx.doi.org/10.1016/j.bbapap.2005.03.005.

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30

Sierra-Valdez, Francisco, Caleigh M. Azumaya, Luis O. Romero, Terunaga Nakagawa, and Julio F. Cordero-Morales. "Structure–function analyses of the ion channel TRPC3 reveal that its cytoplasmic domain allosterically modulates channel gating." Journal of Biological Chemistry 293, no. 41 (August 23, 2018): 16102–14. http://dx.doi.org/10.1074/jbc.ra118.005066.

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The transient receptor potential ion channels support Ca2+ permeation in many organs, including the heart, brain, and kidney. Genetic mutations in transient receptor potential cation channel subfamily C member 3 (TRPC3) are associated with neurodegenerative diseases, memory loss, and hypertension. To better understand the conformational changes that regulate TRPC3 function, we solved the cryo-EM structures for the full-length human TRPC3 and its cytoplasmic domain (CPD) in the apo state at 5.8- and 4.0-Å resolution, respectively. These structures revealed that the TRPC3 transmembrane domain resembles those of other TRP channels and that the CPD is a stable module involved in channel assembly and gating. We observed the presence of a C-terminal domain swap at the center of the CPD where horizontal helices (HHs) transition into a coiled-coil bundle. Comparison of TRPC3 structures revealed that the HHs can reside in two distinct positions. Electrophysiological analyses disclosed that shortening the length of the C-terminal loop connecting the HH with the TRP helices increases TRPC3 activity and that elongating the length of the loop has the opposite effect. Our findings indicate that the C-terminal loop affects channel gating by altering the allosteric coupling between the cytoplasmic and transmembrane domains. We propose that molecules that target the HH may represent a promising strategy for controlling TRPC3-associated neurological disorders and hypertension.

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31

Vranken, Wim F., Miloš Buděšínský, Franky Fant, Kris Boulez, Hélène Gras-Masse, and Frans A. M. Borremans. "Conformational Features of a Synthetic Cyclic Peptide Corresponding to the Complete V3 Loop of the ELI HIV-1 Strain in Water." Collection of Czechoslovak Chemical Communications 61, no. 5 (1996): 742–50. http://dx.doi.org/10.1135/cccc19960742.

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The disulfide bridge closed cyclic peptide corresponding to the whole V3 loop of the envelope protein gp120 of the ELI HIV-1 strain was synthesized and examined by proton 2D NMR spectroscopy in water. Although the peptide is mainly conformationally flexible, a turn appears to be present at an N-terminal glycosylation site, while in the C-terminal half of the peptide the data point toward nascent helical structures. Similar conformational preferences in aqueous solution were observed in other V3 loop peptides, especially for the Ile28-Gly30 tripeptide part.

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32

Chan, Tung O., Jin Zhang, Brian C. Tiegs, Brian Blumhof, Linda Yan, Nikhil Keny, Morgan Penny, et al. "Akt kinase C-terminal modifications control activation loop dephosphorylation and enhance insulin response." Biochemical Journal 471, no. 1 (September 21, 2015): 37–51. http://dx.doi.org/10.1042/bj20150325.

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This report identifies an allosteric regulatory mechanism involving C-terminal sequences and the Akt kinase domain that serves to restrict phosphatase access to the Akt activation loop. Importantly, this interaction can be modified to increase insulin sensitivity and protect cells from ceramide-mediated insulin resistance.

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33

Barski, Oleg A., Kenneth H. Gabbay, and Kurt M. Bohren. "The C-Terminal Loop of Aldehyde Reductase Determines the Substrate and Inhibitor Specificity†." Biochemistry 35, no. 45 (January 1996): 14276–80. http://dx.doi.org/10.1021/bi9619740.

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34

Chen, Yi-Chun, Yao-Tsung Chang, Chiu-Yueh Chen, Jia-Hau Shiu, Chun-Ho Cheng, Chun-Hao Huang, Ju-Fei Chen, and Woei-Jer Chuang. "Structural Insight into Integrin Recognition and Anticancer Activity of Echistatin." Toxins 12, no. 11 (November 9, 2020): 709. http://dx.doi.org/10.3390/toxins12110709.

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Echistatin (Ech) is a short disintegrin with a long 42NPHKGPAT C-terminal tail. We determined the 3-D structure of Ech by X-ray crystallography. Superimposition of the structures of chains A and B showed conformational differences in their RGD loops and C-termini. The chain A structure is consistent with our NMR analysis that the GPAT residues of the C-terminus cannot be observed due to high flexibility. The hydrogen bond patterns of the RGD loop and between the RGD loop and C-terminus in Ech were the same as those of the corresponding residues in medium disintegrins. The mutant with C-terminal HKGPAT truncation caused 6.4-, 7.0-, 11.7-, and 18.6-fold decreases in inhibiting integrins αvβ3, αIIbβ3, αvβ5, and α5β1. Mutagenesis of the C-terminus showed that the H44A mutant caused 2.5- and 4.4-fold increases in inhibiting αIIbβ3 and α5β1, and the K45A mutant caused a 2.6-fold decrease in inhibiting αIIbβ3. We found that Ech inhibited VEGF-induced HUVEC proliferation with an IC50 value of 103.2 nM and inhibited the migration of A375, U373MG, and Panc-1 tumor cells with IC50 values of 1.5, 5.7, and 154.5 nM. These findings suggest that Ech is a potential anticancer agent, and its C-terminal region can be optimized to improve its anticancer activity.

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Peverelli, Erika, Giovanna Mantovani, Davide Calebiro, Andrea Doni, Sara Bondioni, Andrea Lania, Paolo Beck-Peccoz, and Anna Spada. "The Third Intracellular Loop of the Human Somatostatin Receptor 5 Is Crucial for Arrestin Binding and Receptor Internalization after Somatostatin Stimulation." Molecular Endocrinology 22, no. 3 (March 1, 2008): 676–88. http://dx.doi.org/10.1210/me.2007-0068.

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Abstract Somatostatin (SS) is a widely distributed polypeptide that exerts inhibitory effects on hormone secretion and cell proliferation by interacting with five different receptors (SST1-SST5). β-Arrestins have been implicated in regulating SST internalization, but the structural domains mediating this effect are largely unknown. The aim of this study was to characterize the intracellular mechanisms responsible for internalization of human SST5 in the rat pituitary cell line GH3 and to identify the SST5 structural domains involved in this process. To this purpose we evaluated, by fluorescence microscopy and biochemical assay, the ability of wild-type, progressive C-terminal truncated and third cytoplasmatic loop mutants SST5-DsRed to associate with β-arrestin-enhanced green fluorescent protein and to internalize under SS28 stimulation. The truncated mutants were comparable to the wild-type receptor with respect to recruitment of β-arrestin-2 and internalization, whereas the third loop mutants R240W, S242A, and T247A showed the abolishment or reduction of arrestin association and a significant reduction of receptor internalization (14.4%, 29%, and 30.9% vs. 52.4% of wild type) and serine phosphorylation upon SS28 stimulation. Moreover, we evaluated the ability of simultaneous mutation of these three residues (R240, S242, and T247) and C-terminal truncated receptors to internalize. The progressive truncation of the C-terminal tail resulted in a progressive increased internalization (21.6%, 36.7%, and 41%, respectively) with respect to the full-length total third-loop mutant (15%). In conclusion, our results indicate the SST5 third intracellular loop as an important mediator of β-arrestin/receptor interaction and receptor internalization, whereas they suggest that residues 328–347 within the C terminus may play an inhibitory role in receptor internalization.

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Law, Ruby H. P., Trifina Sofian, Wan-Ting Kan, Anita J. Horvath, Corinne R. Hitchen, Christopher G. Langendorf, Ashley M. Buckle, James C. Whisstock, and Paul B. Coughlin. "X-ray crystal structure of the fibrinolysis inhibitor α2-antiplasmin." Blood 111, no. 4 (February 15, 2008): 2049–52. http://dx.doi.org/10.1182/blood-2007-09-114215.

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The serpin α2-antiplasmin (SERPINF2) is the principal inhibitor of plasmin and inhibits fibrinolysis. Accordingly, α2-antiplasmin deficiency in humans results in uncontrolled fibrinolysis and a bleeding disorder. α2-antiplasmin is an unusual serpin, in that it contains extensive N- and C-terminal sequences flanking the serpin domain. The N-terminal sequence is crosslinked to fibrin by factor XIIIa, whereas the C-terminal region mediates the initial interaction with plasmin. To understand how this may happen, we have determined the 2.65Å X-ray crystal structure of an N-terminal truncated murine α2-antiplasmin. The structure reveals that part of the C-terminal sequence is tightly associated with the body of the serpin. This would be anticipated to position the flexible plasmin-binding portion of the C-terminus in close proximity to the serpin Reactive Center Loop where it may act as a template to accelerate serpin/protease interactions.

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Zhou, Zi-Ren, Yu-Hang Zhang, Shuai Liu, Ai-Xin Song, and Hong-Yu Hu. "Length of the active-site crossover loop defines the substrate specificity of ubiquitin C-terminal hydrolases for ubiquitin chains." Biochemical Journal 441, no. 1 (December 14, 2011): 143–49. http://dx.doi.org/10.1042/bj20110699.

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UCHs [Ub (ubiquitin) C-terminal hydrolases] are a family of deubiquitinating enzymes that are often thought to only remove small C-terminal peptide tails from Ub adducts. Among the four UCHs identified to date, neither UCH-L3 nor UCH-L1 can catalyse the hydrolysis of isopeptide Ub chains, but UCH-L5 can when it is present in the PA700 complex of the proteasome. In the present paper, we report that the UCH domain of UCH-L5, different from UCH-L1 and UCH-L3, by itself can process the K48-diUb (Lys48-linked di-ubiquitin) substrate by cleaving the isopeptide bond between two Ub units. The catalytic specificity of the four UCHs is dependent on the length of the active-site crossover loop. The UCH domain with a long crossover loop (usually >14 residues), such as that of UCH-L5 or BAP1 [BRCA1 (breast cancer early-onset 1)-associated protein 1], is able to cleave both small and large Ub derivatives, whereas the one with a short loop can only process small Ub derivatives. We also found that elongation of the crossover loop enables UCH-L1 to have isopeptidase activity for K48-diUb in a length-dependent manner. Thus the loop length of UCHs defines their substrate specificity for diUb chains, suggesting that the chain flexibility of the crossover loop plays an important role in determining its catalytic activity and substrate specificity for cleaving isopeptide Ub chains.

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Wang, Fanghua, Ruixia Wei, Abdelkarim Abousalham, Wuchong Chen, Bo Yang, and Yonghua Wang. "Effect of N- and C-Terminal Amino Acids on the Interfacial Binding Properties of Phospholipase D from Vibrio parahaemolyticus." International Journal of Molecular Sciences 19, no. 8 (August 19, 2018): 2447. http://dx.doi.org/10.3390/ijms19082447.

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The effects of N-terminal (1–34 amino acids) and C-terminal (434–487 amino acids) amino acid sequences on the interfacial binding properties of Phospholipase D from Vibrio parahaemolyticus (VpPLD) were characterized by using monomolecular film technology. Online tools allowed the prediction of the secondary structure of the target N- and C-terminal VpPLD sequences. Various truncated forms of VpPLD with different N- or C-terminal deletions were designed, based on their secondary structure, and their membrane binding properties were examined. The analysis of the maximum insertion pressure (MIP) and synergy factor “a” indicated that the loop structure (1–25 amino acids) in the N-terminal segment of VpPLD had a positive effect on the binding of VpPLD to phospholipid monolayers, especially to 1,2-dimyristoyl-sn-glycero-3-phosphoserine and 1,2-dimyristoyl-sn-glycero-3-phosphocholine. The deletion affecting the N-terminus loop structure caused a significant decrease of the MIP and synergy factor a of the protein for these phospholipid monolayers. Conversely, the deletion of the helix structure (26–34 amino acids) basically had no influence on the binding of VpPLD to phospholipid monolayers. The deletion of the C-terminal amino acids 434–487 did not significantly change the binding selectivity of VpPLD for the various phospholipid monolayer tested here. However, a significant increase of the MIP value for all the phospholipid monolayers strongly indicated that the three-strand segment (434–469 amino acids) had a great negative effect on the interfacial binding to these phospholipid monolayers. The deletion of this peptide caused a significantly greater insertion of the protein into the phospholipid monolayers examined. The present study provides detailed information on the effect of the N- and C-terminal segments of VpPLD on the interfacial binding properties of the enzyme and improves our understanding of the interactions between this enzyme and cell membranes.

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SADLISH, Heather, Frederick M. R. WILLIAMS, and Wayne F. FLINTOFF. "Cytoplasmic domains of the reduced folate carrier are essential for trafficking, but not function." Biochemical Journal 364, no. 3 (June 15, 2002): 777–86. http://dx.doi.org/10.1042/bj20011361.

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The reduced folate carrier (RFC) protein has a secondary structure consistent with the predicted 12 transmembrane (TM) domains, intracellular N- and C-termini and a large cytoplasmic loop between TM6 and TM7. In the present study, the role of the cytoplasmic domains in substrate transport and protein biogenesis were examined using an array of hamster RFC deletion mutants fused to enhanced green fluorescent protein and expressed in Chinese hamster ovary cells. The N- and C-terminal tails were removed both individually and together, or the large cytoplasmic loop was modified such that the domain size and role of conserved sequences could be examined. The loss of the N- or C-terminal tails did not appear to significantly disrupt protein function, although both termini appeared to have a role in the efficiency with which molecules exited the endoplasmic reticulum to localize at the plasma membrane. There appeared to be both size and sequence requirements for the intracellular loop, which are able to drastically affect protein stability and function unless met. Furthermore, there might be an indirect role for the loop in substrate translocation, since even moderate changes significantly reduced the Vmax for methotrexate transport. Although these cytoplasmic domains do not appear to be absolutely essential for substrate transport, each one is important for biogenesis and localization.

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Senda, Yoshie, Naoko Murata‐Kamiya, and Masanori Hatakeyama. "C‐terminal Src kinase‐mediated EPIYA phosphorylation of Pragmin creates a feed‐forward C‐terminal Src kinase activation loop that promotes cell motility." Cancer Science 107, no. 7 (June 13, 2016): 972–80. http://dx.doi.org/10.1111/cas.12962.

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Carlberg, K., and L. Rohrschneider. "The effect of activating mutations on dimerization, tyrosine phosphorylation and internalization of the macrophage colony stimulating factor receptor." Molecular Biology of the Cell 5, no. 1 (January 1994): 81–95. http://dx.doi.org/10.1091/mbc.5.1.81.

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Oncogenic activation of the macrophage colony stimulating factor (M-CSF) receptor (c-Fms) requires mutation or truncation of the carboxyl terminus and specific amino acid substitutions in or near the fourth immunoglobulin (Ig)-like loop in the extracellular domain. Using a murine c-Fms system, we investigated the effect of C-terminal truncation, substitutions at amino acids 301 and 374 in the fourth Ig-like loop of the extracellular domain, or the combined mutations on individual steps in receptor activation. The mutations at amino acids 301 and 374 were necessary, but not sufficient, for receptor dimerization in the absence of M-CSF. Only receptors with a truncated C-terminus as well as the extracellular domain mutations dimerized efficiently in the absence of M-CSF, suggesting that the C-terminus of c-Fms also regulates receptor oligomerization. Truncation of the C-terminus alone did not cause receptor dimerization and did not activate the kinase enzymatic activity. Thus, truncation of the C-terminus did not activate receptor monomers in cis. Receptors with both a truncated C-terminus and the extracellular domain mutations underwent ligand-independent aggregation, transphosphorylation, and phosphorylation of cellular proteins, followed by rapid internalization and degradation. These results suggest that M-CSF binding to c-Fms initiates activation by inducing conformational changes in both the cytoplasmic C-terminal domain and the fourth Ig-like loop of the extracellular domain, leading to the formation of stable receptor dimers.

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Maerz, Anne L., Heidi E. Drummer, Kirilee A. Wilson, and Pantelis Poumbourios. "Functional Analysis of the Disulfide-Bonded Loop/Chain Reversal Region of Human Immunodeficiency Virus Type 1 gp41 Reveals a Critical Role in gp120-gp41 Association." Journal of Virology 75, no. 14 (July 15, 2001): 6635–44. http://dx.doi.org/10.1128/jvi.75.14.6635-6644.2001.

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ABSTRACT Human immunodeficiency virus type 1 (HIV-1) entry into cells is mediated by the surface-exposed envelope protein (SU) gp120, which binds to cellular CD4 and chemokine receptors, triggering the membrane fusion activity of the transmembrane (TM) protein gp41. The core of gp41 comprises an N-terminal triple-stranded coiled coil and an antiparallel C-terminal helical segment which is packed against the exterior of the coiled coil and is thought to correspond to a fusion-activated conformation. The available gp41 crystal structures lack the conserved disulfide-bonded loop region which, in human T-lymphotropic virus type 1 (HTLV-1) and murine leukemia virus TM proteins, mediates a chain reversal, connecting the antiparallel N- and C-terminal regions. Mutations in the HTLV-1 TM protein gp21 disulfide-bonded loop/chain reversal region adversely affected fusion activity without abolishing SU-TM association (A. L. Maerz, R. J. Center, B. E. Kemp, B. Kobe, and P. Poumbourios, J. Virol. 74:6614–6621, 2000). We now report that in contrast to our findings with HTLV-1, conservative substitutions in the HIV-1 gp41 disulfide-bonded loop/chain reversal region abolished association with gp120. While the mutations affecting gp120-gp41 association also affected cell-cell fusion activity, HIV-1 glycoprotein maturation appeared normal. The mutant glycoproteins were processed, expressed at the cell surface, and efficiently immunoprecipitated by conformation-dependent monoclonal antibodies. The gp120 association site includes aromatic and hydrophobic residues on either side of the gp41 disulfide-bonded loop and a basic residue within the loop. The HIV-1 gp41 disulfide-bonded loop/chain reversal region is a critical gp120 contact site; therefore, it is also likely to play a central role in fusion activation by linking CD4 plus chemokine receptor-induced conformational changes in gp120 to gp41 fusogenicity. These gp120 contact residues are present in diverse primate lentiviruses, suggesting conservation of function.

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Pearson, Adam J., Paul Fullwood, Gabriela Toro Tapia, Ian Prise, Michael P. Smith, Qiuping Xu, Allan Jordan, et al. "Discovery of a Gatekeeper Residue in the C-Terminal Tail of the Extracellular Signal-Regulated Protein Kinase 5 (ERK5)." International Journal of Molecular Sciences 21, no. 3 (January 31, 2020): 929. http://dx.doi.org/10.3390/ijms21030929.

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The extracellular signal-regulated protein kinase 5 (ERK5) is a non-redundant mitogen-activated protein kinase (MAPK) that exhibits a unique C-terminal extension which comprises distinct structural and functional properties. Here, we sought to elucidate the significance of phosphoacceptor sites in the C-terminal transactivation domain of ERK5. We have found that Thr732 acted as a functional gatekeeper residue controlling C-terminal-mediated nuclear translocation and transcriptional enhancement. Consistently, using a non-bias quantitative mass spectrometry approach, we demonstrated that phosphorylation at Thr732 conferred selectivity for binding interactions of ERK5 with proteins related to chromatin and RNA biology, whereas a number of metabolic regulators were associated with full-length wild type ERK5. Additionally, our proteomic analysis revealed that phosphorylation of the Ser730-Glu-Thr732-Pro motif could occur independently of dual phosphorylation at Thr218-Glu-Tyr220 in the activation loop. Collectively, our results firmly establish the significance of C-terminal phosphorylation in regulating ERK5 function. The post-translational modification of ERK5 on its C-terminal tail might be of particular relevance in cancer cells where ERK5 has be found to be hyperphosphoryated.

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Ishii, K., H. Hayashi, M. Todaka, S. Kamohara, F. Kanai, H. Jinnouchi, L. Wang, and Y. Ebina. "Possible domains responsible for intracellular targeting and insulin-dependent translocation of glucose transporter type 4." Biochemical Journal 309, no. 3 (August 1, 1995): 813–23. http://dx.doi.org/10.1042/bj3090813.

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Translocation of the type 4 glucose transporter (GLUT4) to the cell surface from an intracellular pool is the major mechanism of insulin-stimulated glucose uptake in insulin-target cells. We developed a highly sensitive and quantitative method to detect GLUT4 immunologically on the surface of intact cells, using c-myc epitope-tagged GLUT4 (GLUT4myc). We constructed c-myc epitope-tagged glucose transporter type 1 (GLUT1myc) and found that the GLUT1myc was also translocated to the cell surface of Chinese hamster ovary cells, 3T3-L1 fibroblasts and NIH 3T3 cells, in response to insulin, but the degree of translocation was less than that of GLUT4myc. Since GLUT1 and GLUT4 have different intracellular distributions and different degrees of insulin-stimulated translocation, we examined the domains of GLUT4, using c-myc epitope-tagged chimeric glucose transporters between these two isoforms. The results indicated that, (1) all the cytoplasmic N-terminal region, middle intracellular loop and cytoplasmic C-terminal region of GLUT4 have independent intracellular targeting signals, (2) these sequences for intracellular targeting of GLUT4 were not sufficient to determine GLUT4 translocation in response to insulin, and (3) the N-terminal half of GLUT4 devoid both of cytoplasmic N-terminus and of middle intracellular loop seems to be necessary for insulin-stimulated GLUT4 translocation.

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Labrosse, Béatrice, Carole Treboute, Anne Brelot, and Marc Alizon. "Cooperation of the V1/V2 and V3 Domains of Human Immunodeficiency Virus Type 1 gp120 for Interaction with the CXCR4 Receptor." Journal of Virology 75, no. 12 (June 15, 2001): 5457–64. http://dx.doi.org/10.1128/jvi.75.12.5457-5464.2001.

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ABSTRACT Human immunodeficiency virus type 1 (HIV-1) entry is triggered by the interaction of the gp120 envelope glycoprotein with a cellular chemokine receptor, either CCR5 or CXCR4. We have identified different mutations in human CXCR4 that prevent efficient infection by one HIV-1 strain (NDK) but not another (LAI) and sought to define these strain-dependent effects at the gp120 level. The lack of activity toward the NDK strain of the HHRH chimeric CXCR4 in which the second extracellular loop (ECL2) derived from the rat CXCR4 and of CXCR4 with mutations at an aspartic acid in ECL2 (D193A and D193R) was apparently due to the sequence of the third variable loop (V3) of gp120, more precisely, to its C-terminal part. Indeed, substitution of the LAI V3 loop or only its C-terminal part in the NDK gp 120 context was sufficient to restore usage of the HHRH, D193A, and D193R receptors. The same result was achieved upon mutation of a single lysine residue of the NDK V3 loop to alanine (K319A) but not to arginine (K319R). These results provide a strong case for a direct interaction between the gp120 V3 loop and the ECL2 domain of CXCR4. By contrast, V3 substitutions had no effect on the inability of NDK to infect cells via a mutant CXCR4 in which the amino-terminal extracellular domain (NT) is deleted. In experiments with a set of chimeric NDK-LAI gp120s, the V1/V2 region from LAI gp120 was both necessary and sufficient for usage of the NT-deleted CXCR4. Different variable domains of gp120 can therefore cooperate for a functional interaction with CXCR4.

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Terasawa, Kazuya, Katsuhiko Yoshimatsu, Shun-ichiro Iemura, Tohru Natsume, Keiji Tanaka, and Yasufumi Minami. "Cdc37 Interacts with the Glycine-Rich Loop of Hsp90 Client Kinases." Molecular and Cellular Biology 26, no. 9 (May 1, 2006): 3378–89. http://dx.doi.org/10.1128/mcb.26.9.3378-3389.2006.

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ABSTRACT Recently, we identified a client-binding site of Cdc37 that is required for its association with protein kinases. Phage display technology and liquid chromatography-tandem mass spectrometry (which identifies a total of 33 proteins) consistently identify a unique sequence, GXFG, as a Cdc37-interacting motif that occurs in the canonical glycine-rich loop (GXGXXG) of protein kinases, regardless of their dependence on Hsp90 or Cdc37. The glycine-rich motif of Raf-1 (GSGSFG) is necessary for its association with Cdc37; nevertheless, the N lobe of Raf-1 (which includes the GSGSFG motif) on its own cannot interact with Cdc37. Chimeric mutants of Cdk2 and Cdk4, which differ sharply in their affinities toward Cdc37, show that their C-terminal portions may determine this difference. In addition, a nonclient kinase, the catalytic subunit of cyclic AMP-dependent protein kinase, interacts with Cdc37 but only when a threonine residue in the activation segment of its C lobe is unphosphorylated. Thus, although a region in the C termini of protein kinases may be crucial for accomplishing and maintaining their interaction with Cdc37, we conclude that the N-terminal glycine-rich loop of protein kinases is essential for physically associating with Cdc37.

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Almond, David, Chavdar Krachmarov, James Swetnam, Susan Zolla-Pazner, and Timothy Cardozo. "Resistance of Subtype C HIV-1 Strains to Anti-V3 Loop Antibodies." Advances in Virology 2012 (2012): 1–8. http://dx.doi.org/10.1155/2012/803535.

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HIV-1’s subtype C V3 loop consensus sequence exhibits increased resistance to anti-V3 antibody-mediated neutralization as compared to the subtype B consensus sequence. The dynamic 3D structure of the consensus C V3 loop crown, visualized byab initiofolding, suggested that the resistance derives from structural rigidity and non-β-strand secondary protein structure in the N-terminal strand of theβ-hairpin of the V3 loop crown, which is where most known anti-V3 loop antibodies bind. The observation of either rigidity or non-β-strand structure in this region correlated with observed resistance to antibody-mediated neutralization in a series of chimeric pseudovirus (psV) mutants. The results suggest the presence of an epitope-independent, neutralization-relevant structural difference in the antibody-targeted region of the V3 loop crown between subtype C and subtype B, a difference that we hypothesize may contribute to the divergent pattern of global spread between these subtypes. As antibodies to a variable loop were recently identified as an inverse correlate of risk for HIV infection, the structure-function relationships discussed in this study may have relevance to HIV vaccine research.

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Rubenstein, Eric M., Rhonda R. McCartney, and Martin C. Schmidt. "Regulatory Domains of Snf1-Activating Kinases Determine Pathway Specificity." Eukaryotic Cell 5, no. 4 (April 2006): 620–27. http://dx.doi.org/10.1128/ec.5.4.620-627.2006.

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ABSTRACT In Saccharomyces cerevisiae, the Snf1 kinase can be activated by any one of three upstream kinases, Sak1, Tos3, or Elm1. All three Snf1-activating kinases contain serine/threonine kinase domains near their N termini and large C-terminal domains with little sequence conservation and previously unknown function. Deletion of the C-terminal domains of Sak1 and Tos3 greatly reduces their ability to activate the Snf1 pathway. In contrast, deletion of the Elm1 C-terminal domain has no effect on Snf1 signaling but abrogates the ability of Elm1 to participate in the morphogenetic-checkpoint signaling pathway. Thus, the C-terminal domains of Sak1, Tos3, and Elm1 help to determine pathway specificity. Additional deletion mutants of the Sak1 kinase revealed that the N terminus of the protein is essential for Snf1 signaling. The deletion of 43 amino acids from within the N terminus of Sak1 (residues 87 to 129) completely blocks Snf1 signaling and activation loop phosphorylation in vivo. The Sak1 kinase domain (lacking both N-terminal and C-terminal domains) is catalytically active and specific in vitro but is unable to promote Snf1 signaling in vivo when expressed at normal levels. Our studies indicate that the kinase domains of the Snf1-activating kinases are not sufficient by themselves for their proper function and that the nonconserved N-terminal and C-terminal domains are critical for the biological activities of these kinases.

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Guimaraes, Carla P., Martin D. Witte, Christopher S. Theile, Gunes Bozkurt, Lenka Kundrat, Annet E. M. Blom, and Hidde L. Ploegh. "Site-specific C-terminal and internal loop labeling of proteins using sortase-mediated reactions." Nature Protocols 8, no. 9 (August 29, 2013): 1787–99. http://dx.doi.org/10.1038/nprot.2013.101.

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Raja, M. Mobeen, and Rolf K. H. Kinne. "Interaction of C-Terminal Loop 13 of Sodium-Glucose Cotransporter SGLT1 with Lipid Bilayers†." Biochemistry 44, no. 25 (June 2005): 9123–29. http://dx.doi.org/10.1021/bi050323d.

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Journal articles on the topic 'C-terminal loop'

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