Journal articles: 'GYF domain'

1

Kofler, Michael M., and Christian Freund. "The GYF domain." FEBS Journal 273, no. 2 (January 2006): 245–56. http://dx.doi.org/10.1111/j.1742-4658.2005.05078.x.

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Zhang, Xiaobo, Lei Qin, Junxing Lu, Yunong Xia, Xianyu Tang, Xun Lu, and Shitou Xia. "Genome-Wide Identification of GYF-Domain Encoding Genes in Three Brassica Species and Their Expression Responding to Sclerotinia sclerotiorum in Brassica napus." Genes 14, no. 1 (January 15, 2023): 224. http://dx.doi.org/10.3390/genes14010224.

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GYF (glycine-tyrosine-phenylalanine)-domain-containing proteins, which were reported to participate in many aspects of biological processes in yeast and animals, are highly conserved adaptor proteins existing in almost all eukaryotes. Our previous study revealed that GYF protein MUSE11/EXA1 is involved in nucleotide-binding leucine-rich repeat (NLR) receptor-mediated defense in Arabidopsis thaliana. However, the GYF-domain encoding homologous genes are still not clear in other plants. Here, we performed genome-wide identification of GYF-domain encoding genes (GYFs) from Brassica napus and its parental species, Brassica rapa and Brassica oleracea. As a result, 26 GYFs of B. napus (BnaGYFs), 11 GYFs of B. rapa (BraGYFs), and 14 GYFs of B. oleracea (BolGYFs) together with 10 A. thaliana (AtGYFs) were identified, respectively. We, then, conducted gene structure, motif, cis-acting elements, duplication, chromosome localization, and phylogenetic analysis of these genes. Gene structure analysis indicated the diversity of the exon numbers of these genes. We found that the defense and stress responsiveness element existed in 23 genes and also identified 10 motifs in these GYF proteins. Chromosome localization exhibited a similar distribution of BnaGYFs with BraGYFs or BolGYFs in their respective genomes. The phylogenetic and gene collinearity analysis showed the evolutionary conservation of GYFs among B. napus and its parental species as well as Arabidopsis. These 61 identified GYF domain proteins can be classified into seven groups according to their sequence similarity. Expression of BnaGYFs induced by Sclerotinia sclerotiorum provided five highly upregulated genes and five highly downregulated genes, which might be candidates for further research of plant–fungal interaction in B. napus.

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Mayya, Vinay K., Mathieu N. Flamand, Alice M. Lambert, Seyed Mehdi Jafarnejad, James A. Wohlschlegel, Nahum Sonenberg, and Thomas F. Duchaine. "microRNA-mediated translation repression through GYF-1 and IFE-4 in C. elegans development." Nucleic Acids Research 49, no. 9 (March 24, 2021): 4803–15. http://dx.doi.org/10.1093/nar/gkab162.

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Abstract microRNA (miRNA)-mediated gene silencing is enacted through the recruitment of effector proteins that direct translational repression or degradation of mRNA targets, but the relative importance of their activities for animal development remains unknown. Our concerted proteomic surveys identified the uncharacterized GYF-domain encoding protein GYF-1 and its direct interaction with IFE-4, the ortholog of the mammalian translation repressor 4EHP, as key miRNA effector proteins in Caenorhabditis elegans. Recruitment of GYF-1 protein to mRNA reporters in vitro or in vivo leads to potent translation repression without affecting the poly(A) tail or impinging on mRNA stability. Loss of gyf-1 is synthetic lethal with hypomorphic alleles of embryonic miR-35–42 and larval (L4) let-7 miRNAs, which is phenocopied through engineered mutations in gyf-1 that abolish interaction with IFE-4. GYF-1/4EHP function is cascade-specific, as loss of gyf-1 had no noticeable impact on the functions of other miRNAs, including lin-4 and lsy-6. Overall, our findings reveal the first direct effector of miRNA-mediated translational repression in C. elegans and its physiological importance for the function of several, but likely not all miRNAs.

4

Kofler, Michael, Kathrin Motzny, Michael Beyermann, and Christian Freund. "Novel Interaction Partners of the CD2BP2-GYF Domain." Journal of Biological Chemistry 280, no. 39 (July 6, 2005): 33397–402. http://dx.doi.org/10.1074/jbc.m503989200.

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Mansour, Hala, Alejandro Cabezas-Cruz, Véronique Peucelle, Amaury Farce, Sophie Salomé-Desnoulez, Ines Metatla, Ida Chiara Guerrera, Thomas Hollin, and Jamal Khalife. "Characterization of GEXP15 as a Potential Regulator of Protein Phosphatase 1 in Plasmodium falciparum." International Journal of Molecular Sciences 24, no. 16 (August 10, 2023): 12647. http://dx.doi.org/10.3390/ijms241612647.

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The Protein Phosphatase type 1 catalytic subunit (PP1c) (PF3D7_1414400) operates in combination with various regulatory proteins to specifically direct and control its phosphatase activity. However, there is little information about this phosphatase and its regulators in the human malaria parasite, Plasmodium falciparum. To address this knowledge gap, we conducted a comprehensive investigation into the structural and functional characteristics of a conserved Plasmodium-specific regulator called Gametocyte EXported Protein 15, GEXP15 (PF3D7_1031600). Through in silico analysis, we identified three significant regions of interest in GEXP15: an N-terminal region housing a PP1-interacting RVxF motif, a conserved domain whose function is unknown, and a GYF-like domain that potentially facilitates specific protein–protein interactions. To further elucidate the role of GEXP15, we conducted in vitro interaction studies that demonstrated a direct interaction between GEXP15 and PP1 via the RVxF-binding motif. This interaction was found to enhance the phosphatase activity of PP1. Additionally, utilizing a transgenic GEXP15-tagged line and live microscopy, we observed high expression of GEXP15 in late asexual stages of the parasite, with localization predominantly in the nucleus. Immunoprecipitation assays followed by mass spectrometry analyses revealed the interaction of GEXP15 with ribosomal- and RNA-binding proteins. Furthermore, through pull-down analyses of recombinant functional domains of His-tagged GEXP15, we confirmed its binding to the ribosomal complex via the GYF domain. Collectively, our study sheds light on the PfGEXP15–PP1–ribosome interaction, which plays a crucial role in protein translation. These findings suggest that PfGEXP15 could serve as a potential target for the development of malaria drugs.

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Kofler, Michael, Kathrin Motzny, and Christian Freund. "GYF Domain Proteomics Reveals Interaction Sites in Known and Novel Target Proteins." Molecular & Cellular Proteomics 4, no. 11 (August 23, 2005): 1797–811. http://dx.doi.org/10.1074/mcp.m500129-mcp200.

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Albert, Gesa I., Christoph Schell, Karin M. Kirschner, Sebastian Schäfer, Ronald Naumann, Alexandra Müller, Oliver Kretz, et al. "The GYF domain protein CD2BP2 is critical for embryogenesis and podocyte function." Journal of Molecular Cell Biology 7, no. 5 (June 16, 2015): 402–14. http://dx.doi.org/10.1093/jmcb/mjv039.

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Gu, Wei, Michael Kofler, Iris Antes, Christian Freund, and Volkhard Helms. "Alternative Binding Modes of Proline-Rich Peptides Binding to the GYF Domain†." Biochemistry 44, no. 17 (May 2005): 6404–15. http://dx.doi.org/10.1021/bi0479914.

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9

Opitz, Robert, Matthias Müller, Cédric Reuter, Matthias Barone, Arne Soicke, Yvette Roske, Kirill Piotukh, et al. "A modular toolkit to inhibit proline-rich motif–mediated protein–protein interactions." Proceedings of the National Academy of Sciences 112, no. 16 (April 6, 2015): 5011–16. http://dx.doi.org/10.1073/pnas.1422054112.

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Small-molecule competitors of protein–protein interactions are urgently needed for functional analysis of large-scale genomics and proteomics data. Particularly abundant, yet so far undruggable, targets include domains specialized in recognizing proline-rich segments, including Src-homology 3 (SH3), WW, GYF, and Drosophila enabled (Ena)/vasodilator-stimulated phosphoprotein (VASP) homology 1 (EVH1) domains. Here, we present a modular strategy to obtain an extendable toolkit of chemical fragments (ProMs) designed to replace pairs of conserved prolines in recognition motifs. As proof-of-principle, we developed a small, selective, peptidomimetic inhibitor of Ena/VASP EVH1 domain interactions. Highly invasive MDA MB 231 breast-cancer cells treated with this ligand showed displacement of VASP from focal adhesions, as well as from the front of lamellipodia, and strongly reduced cell invasion. General applicability of our strategy is illustrated by the design of an ErbB4-derived ligand containing two ProM-1 fragments, targeting the yes-associated protein 1 (YAP1)-WW domain with a fivefold higher affinity.

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Kofler, Michael, Katja Heuer, Tobias Zech, and Christian Freund. "Recognition Sequences for the GYF Domain Reveal a Possible Spliceosomal Function of CD2BP2." Journal of Biological Chemistry 279, no. 27 (April 22, 2004): 28292–97. http://dx.doi.org/10.1074/jbc.m402008200.

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Andujar-Sanchez, Montserrat, Eva S. Cobos, Irene Luque, and Jose C. Martinez. "Thermodynamic Impact of Embedded Water Molecules in the Unfolding of Human CD2BP2-GYF Domain." Journal of Physical Chemistry B 116, no. 24 (June 4, 2012): 7168–75. http://dx.doi.org/10.1021/jp303495b.

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Matsui, Hidenori, Yuko Nomura, Mayumi Egusa, Takahiro Hamada, Gang-Su Hyon, Hironori Kaminaka, Yuichiro Watanabe, et al. "The GYF domain protein PSIG1 dampens the induction of cell death during plant-pathogen interactions." PLOS Genetics 13, no. 10 (October 26, 2017): e1007037. http://dx.doi.org/10.1371/journal.pgen.1007037.

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13

Freund, Christian, Ronald Kühne, Hailin Yang, Sunghyouk Park, Ellis L. Reinherz, and Gerhard Wagner. "Dynamic interaction of CD2 with the GYF and the SH3 domain of compartmentalized effector molecules." EMBO Journal 21, no. 22 (November 15, 2002): 5985–95. http://dx.doi.org/10.1093/emboj/cdf602.

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14

Hashimoto, Masayoshi, Yutaro Neriya, Takuya Keima, Nozomu Iwabuchi, Hiroaki Koinuma, Yuka Hagiwara-Komoda, Kazuya Ishikawa, et al. "EXA1, a GYF domain protein, is responsible for loss-of-susceptibility to plantago asiatica mosaic virus in Arabidopsis thaliana." Plant Journal 88, no. 1 (September 19, 2016): 120–31. http://dx.doi.org/10.1111/tpj.13265.

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15

Meirson, Tomer, David Bomze, Gal Markel, and Abraham O. Samson. "κ-helix and the helical lock and key model: a pivotal way of looking at polyproline II." Bioinformatics 36, no. 12 (March 14, 2020): 3726–32. http://dx.doi.org/10.1093/bioinformatics/btaa186.

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Abstract Motivation Polyproline II (PPII) is a common conformation, comparable to α-helix and β-sheet. PPII, recently termed with a more generic name—κ-helix, adopts a left-handed structure with 3-fold rotational symmetry. Lately, a new type of binding mechanism—the helical lock and key model was introduced in SH3-domain complexes, where the interaction is characterized by a sliding helical pattern. However, whether this binding mechanism is unique only to SH3 domains is unreported. Results Here, we show that the helical binding pattern is a universal feature of the κ-helix conformation, present within all the major target families—SH3, WW, profilin, MHC-II, EVH1 and GYF domains. Based on a geometric analysis of 255 experimentally solved structures, we found that they are characterized by a distinctive rotational angle along the helical axis. Furthermore, we found that the range of helical pitch varies between different protein domains or peptide orientations and that the interaction is also represented by a rotational displacement mimicking helical motion. The discovery of rotational interactions as a mechanism, reveals a new dimension in the realm of protein–protein interactions, which introduces a new layer of information encoded by the helical conformation. Due to the extensive involvement of the conformation in functional interactions, we anticipate our model to expand the current molecular understanding of the relationship between protein structure and function. Availability and implementation We have implemented the proposed methods in an R package freely available at https://github.com/Grantlab/bio3d. Supplementary information Supplementary data are available at Bioinformatics online.

16

Ruscica, Vincenzo, Praveen Bawankar, Daniel Peter, Sigrun Helms, Cátia Igreja, and Elisa Izaurralde. "Direct role for the Drosophila GIGYF protein in 4EHP-mediated mRNA repression." Nucleic Acids Research 47, no. 13 (May 22, 2019): 7035–48. http://dx.doi.org/10.1093/nar/gkz429.

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Abstract The eIF4E-homologous protein (4EHP) is a translational repressor that competes with eIF4E for binding to the 5′-cap structure of specific mRNAs, to which it is recruited by protein factors such as the GRB10-interacting GYF (glycine-tyrosine-phenylalanine domain) proteins (GIGYF). Several experimental evidences suggest that GIGYF proteins are not merely facilitating 4EHP recruitment to transcripts but are actually required for the repressor activity of the complex. However, the underlying molecular mechanism is unknown. Here, we investigated the role of the uncharacterized Drosophila melanogaster (Dm) GIGYF protein in post-transcriptional mRNA regulation. We show that, when in complex with 4EHP, Dm GIGYF not only elicits translational repression but also promotes target mRNA decay via the recruitment of additional effector proteins. We identified the RNA helicase Me31B/DDX6, the decapping activator HPat and the CCR4–NOT deadenylase complex as binding partners of GIGYF proteins. Recruitment of Me31B and HPat via discrete binding motifs conserved among metazoan GIGYF proteins is required for downregulation of mRNA expression by the 4EHP–GIGYF complex. Our findings are consistent with a model in which GIGYF proteins additionally recruit decapping and deadenylation complexes to 4EHP-containing RNPs to induce translational repression and degradation of mRNA targets.

17

Hale, Valerie A., Evan L. Guiney, Lindsey Y. Goldberg, Josephine H. Haduong, Callie S. Kwartler, Katherine W. Scangos, and Caroline Goutte. "Notch Signaling Is Antagonized by SAO-1, a Novel GYF-Domain Protein That Interacts with the E3 Ubiquitin Ligase SEL-10 in Caenorhabditis elegans." Genetics 190, no. 3 (December 29, 2011): 1043–57. http://dx.doi.org/10.1534/genetics.111.136804.

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18

Khosravi-Far, R., M. Chrzanowska-Wodnicka, P. A. Solski, A. Eva, K. Burridge, and C. J. Der. "Dbl and Vav mediate transformation via mitogen-activated protein kinase pathways that are distinct from those activated by oncogenic Ras." Molecular and Cellular Biology 14, no. 10 (October 1994): 6848–57. http://dx.doi.org/10.1128/mcb.14.10.6848-6857.1994.

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Vav and Dbl are members of a novel class of oncogene proteins that share significant sequence identity in a approximately 250-amino-acid domain, designated the Dbl homology domain. Although Dbl functions as a guanine nucleotide exchange factor (GEF) and activator of Rho family proteins, recent evidence has demonstrated that Vav functions as a GEF for Ras proteins. Thus, transformation by Vav and Dbl may be a consequence of constitutive activation of Ras and Rho proteins, respectively. To address this possibility, we have compared the transforming activities of Vav and Dbl with that of the Ras GEF, GRF/CDC25. As expected, GRF-transformed cells exhibited the same reduction in actin stress fibers and focal adhesions as Ras-transformed cells. In contrast, Vav- and Dbl-transformed cells showed the same well-developed stress fibers and focal adhesions observed in normal or RhoA(63L)-transformed NIH 3T3 cells. Furthermore, neither Vav- or Dbl-transformed cells exhibited the elevated levels of Ras-GTP (60%) observed with GRF-transformed cells. Finally, GRF, but not Vav or Dbl, induced transcriptional activation from Ras-responsive DNA elements (ets/AP-1, fos promoter, and kappa B). However, like Ras- and GRF-transformed cells, both Vav- and Dbl-transformed cells exhibited constitutively activated mitogen-activated protein kinases (MAPKs) (primarily p42MAPK/ERK2). Since kinase-deficient forms of p42MAPK/ERK2 and p44MAPK/ERK1 inhibited Dbl transformation, MAPK activation may be an important component of its transforming activity. Taken together, our observations indicate that Vav and Dbl transformation is not a consequence of Ras activation and instead may involve the constitutive activation of MAPKs.

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Khosravi-Far, R., M. Chrzanowska-Wodnicka, P. A. Solski, A. Eva, K. Burridge, and C. J. Der. "Dbl and Vav mediate transformation via mitogen-activated protein kinase pathways that are distinct from those activated by oncogenic Ras." Molecular and Cellular Biology 14, no. 10 (October 1994): 6848–57. http://dx.doi.org/10.1128/mcb.14.10.6848.

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Vav and Dbl are members of a novel class of oncogene proteins that share significant sequence identity in a approximately 250-amino-acid domain, designated the Dbl homology domain. Although Dbl functions as a guanine nucleotide exchange factor (GEF) and activator of Rho family proteins, recent evidence has demonstrated that Vav functions as a GEF for Ras proteins. Thus, transformation by Vav and Dbl may be a consequence of constitutive activation of Ras and Rho proteins, respectively. To address this possibility, we have compared the transforming activities of Vav and Dbl with that of the Ras GEF, GRF/CDC25. As expected, GRF-transformed cells exhibited the same reduction in actin stress fibers and focal adhesions as Ras-transformed cells. In contrast, Vav- and Dbl-transformed cells showed the same well-developed stress fibers and focal adhesions observed in normal or RhoA(63L)-transformed NIH 3T3 cells. Furthermore, neither Vav- or Dbl-transformed cells exhibited the elevated levels of Ras-GTP (60%) observed with GRF-transformed cells. Finally, GRF, but not Vav or Dbl, induced transcriptional activation from Ras-responsive DNA elements (ets/AP-1, fos promoter, and kappa B). However, like Ras- and GRF-transformed cells, both Vav- and Dbl-transformed cells exhibited constitutively activated mitogen-activated protein kinases (MAPKs) (primarily p42MAPK/ERK2). Since kinase-deficient forms of p42MAPK/ERK2 and p44MAPK/ERK1 inhibited Dbl transformation, MAPK activation may be an important component of its transforming activity. Taken together, our observations indicate that Vav and Dbl transformation is not a consequence of Ras activation and instead may involve the constitutive activation of MAPKs.

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Koch, Daniel, Ay Lin Kho, Atsushi Fukuzawa, Alexander Alexandrovich, Kutti J. Vanaanen, Andrew Beavil, Mark Pfuhl, Martin Rees, and Mathias Gautel. "Obscurin Rho GEF domains are phosphorylated by MST-family kinases but do not exhibit nucleotide exchange factor activity towards Rho GTPases in vitro." PLOS ONE 18, no. 4 (April 20, 2023): e0284453. http://dx.doi.org/10.1371/journal.pone.0284453.

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Obscurin is a giant muscle protein (>800 kDa) featuring multiple signalling domains, including an SH3-DH-PH domain triplet from the Trio-subfamily of guanosine nucleotide exchange factors (GEFs). While previous research suggests that these domains can activate the small GTPases RhoA and RhoQ in cells, in vitro characterization of these interactions using biophysical techniques has been hampered by the intrinsic instability of obscurin GEF domains. To study substrate specificity, mechanism and regulation of obscurin GEF function by individual domains, we successfully optimized recombinant production of obscurin GEF domains and found that MST-family kinases phosphorylate the obscurin DH domain at Thr5798. Despite extensive testing of multiple GEF domain fragments, we did not detect any nucleotide exchange activity in vitro against 9 representative small GTPases. Bioinformatic analyses show that obscurin differs from other Trio-subfamily GEFs in several important aspects. While further research is necessary to evaluate obscurin GEF activity in vivo, our results indicate that obscurin has atypical GEF domains that, if catalytically active at all, are subject to complex regulation.

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Buchsbaum, R., J. B. Telliez, S. Goonesekera, and L. A. Feig. "The N-terminal pleckstrin, coiled-coil, and IQ domains of the exchange factor Ras-GRF act cooperatively to facilitate activation by calcium." Molecular and Cellular Biology 16, no. 9 (September 1996): 4888–96. http://dx.doi.org/10.1128/mcb.16.9.4888.

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We have recently shown that the neuronal exchange factor p140 Ras-GRF becomes activated in vivo in response to elevated calcium levels [C. L. Farnsworth, N. W. Freshney, L. B. Rosen, A. Ghosh, M. E. Greenberg, and L. A. Feig, Nature (London) 376:524-527, 1995]. Activation is mediated by calcium-induced calmodulin binding to an IQ domain near the N terminus of Ras-GRF. Here we show that the adjacent N-terminal pleckstrin homology (PH), coiled-coil, and IQ domains function cooperatively to allow Ras-GRF activation. Deletion of the N-terminal PH domain redistributes a large percentage of Ras-GRF from the particulate to the cytosolic fraction of cells and renders the protein insensitive to calcium stimulation. A similar cellular distribution and biological activity are observed when only the core catalytic domain is expressed. Although the PH domain is necessary for particulate association of Ras-GRF, it is not sufficient for targeting the core catalytic domain to this cellular location. This requires the PH domain and the adjacent coiled-coil and IQ sequences. Remarkably, this form of Ras-GRF is constitutively activated. The PH and coiled-coil domains must also perform an additional function, since targeting to the particulate fraction of cells is not sufficient to allow Ras-GRF activation by calcium. A Ras-GRF mutant containing the PH domain from Ras-GTPase-activating protein in place of its own N-terminal PH domain localizes to the particulate fraction of cells but does not respond to calcium. Similar phenotypes are seen with mutant Ras-GRFs containing point mutations in either the PH or coiled-coil domain. These findings argue that the N-terminal PH, coiled-coil, and IQ domains of Ras-GRF function together to connect Ras-GRF to multiple components in the particulate fractions of cells that are required for responsiveness of the protein to calcium signaling.

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Cann, M. J. "Sodium regulation of GAF domain function." Biochemical Society Transactions 35, no. 5 (October 25, 2007): 1032–34. http://dx.doi.org/10.1042/bst0351032.

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Cyclic nucleotide PDEs (phosphodiesterases) regulate cellular levels of cAMP and cGMP by controlling the rate of degradation. Several mammalian PDE isoforms possess N-terminal GAF (found in cGMP PDEs, Anabaena adenylate cyclases and Escherichia coli FhlA; where FhlA is formate hydrogen lyase transcriptional activator) domains that bind cyclic nucleotides. Similarly, the CyaB1 and CyaB2 ACs (adenylate cyclases) of the cyanobacterium Anabaena PCC 7120 bind cAMP through one (CyaB1) or two (CyaB2) N-terminal GAF domains and mediate autoregulation of the AC domain. Sodium inhibits the activity of CyaB1, CyaB2 and mammalian PDE2A in vitro through modulation of GAF domain function. Furthermore, genetic ablation of cyaB1 and cyaB2 gives rise to Anabaena strains defective in homoeostasis at limiting sodium. Sodium regulation of GAF domain function has therefore been conserved since the eukaryotic/prokaryotic divergence. The GAF domain is the first identified protein domain to directly sense and signal changes in environmental sodium.

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Matthiesen, Karina, and Jacob Nielsen. "Binding of cyclic nucleotides to phosphodiesterase 10A and 11A GAF domains does not stimulate catalytic activity." Biochemical Journal 423, no. 3 (October 12, 2009): 401–9. http://dx.doi.org/10.1042/bj20090982.

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To date eleven human PDE (3′,5′-cyclic nucleotide phosphodiesterase) families have been identified. Of these, five families contain non-catalytic tandem GAF (cGMP-specific and -stimulated phosphodiesterases, Anabaenaadenylate cyclases and Escherichia coliFhlA) domains, GAFa and GAFb, in the N-terminal part of the enzyme. For PDE2A, PDE5A and PDE6 the GAF domains have been shown to bind cGMP with high affinity. For PDE2A and PDE5A this ligand binding has been shown to stimulate the catalytic activity of the enzyme. PDE10A and PDE11A are the two most recently described PDEs and it has been suggested that their GAF domains bind to cAMP and cGMP respectively. We have developed a scintillation proximity-based assay to directly measure cyclic nucleotide binding to the PDE2A, PDE10A and PDE11A GAF domains, and in the present study we demonstrate binding of cyclic nucleotides to the PDE10A and PDE11A GAF domains. We show that these non-catalytic sites bind cAMP and cGMP respectively with much higher affinity than has previously been suggested using indirect assessment of the interaction. The GAFb domain of PDE10A binds cAMP with a Kd of 48 nM and the GAFa domain of PDE11A binds cGMP with a Kd of 110 nM. The effect of cyclic nucleotides binding to the GAF domains on the enzyme activity was investigated through the use of modified cyclic nucleotides. In contrast with other GAF domain-containing PDEs, and with what has previously been predicted, ligand binding to the GAF domains of PDE10A and PDE11A does not stimulate catalytic activity.

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Díaz-Benjumea, Rocío, Sunil Laxman, Thomas R. Hinds, Joseph A. Beavo, and Ana Rascón. "Characterization of a novel cAMP-binding, cAMP-specific cyclic nucleotide phosphodiesterase (TcrPDEB1) from Trypanosoma cruzi." Biochemical Journal 399, no. 2 (September 27, 2006): 305–14. http://dx.doi.org/10.1042/bj20060757.

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Trypanosoma cruzi, the causative agent of Chagas disease, encodes a number of different cAMP-specific PDE (phosphodiesterase) families. Here we report the identification and characterization of TcrPDEB1 and its comparison with the previously identified TcrPDEB2 (formerly known as TcPDE1). These are two different PDE enzymes of the TcrPDEB family, named in accordance with the recent recommendations of the Nomenclature Committee for Kinetoplast PDEs [Kunz, Beavo, D'Angelo, Flawia, Francis, Johner, Laxman, Oberholzer, Rascon, Shakur et al. (2006) Mol. Biochem. Parasitol. 145, 133–135]. Both enzymes show resistance to inhibition by many mammalian PDE inhibitors, and those that do inhibit do so with appreciable differences in their inhibitor profiles for the two enzymes. Both enzymes contain two GAF (cGMP-specific and -stimulated phosphodiesterases, Anabaena adenylate cyclases and Escherichia coliFhlA) domains and a catalytic domain highly homologous with that of the T. brucei TbPDE2/TbrPDEB2 family. The N-terminus+GAF-A domains of both enzymes showed significant differences in their affinities for cyclic nucleotide binding. Using a calorimetric technique that allows accurate measurements of low-affinity binding sites, the TcrPDEB2 N-terminus+GAF-A domain was found to bind cAMP with an affinity of ∼500 nM. The TcrPDEB1 N-terminus+GAF-A domain bound cAMP with a slightly lower affinity of ∼1 μM. The N-terminus+GAF-A domain of TcrPDEB1 did not bind cGMP, whereas the N-terminus+GAF-A domain of TcrPDEB2 bound cGMP with a low affinity of ∼3 μM. GAF domains homologous with those found in these proteins were also identified in related trypanosomatid parasites. Finally, a fluorescent cAMP analogue, MANT-cAMP [2′-O-(N-methylanthraniloyl)adenosine-3′,5′-cyclic monophosphate], was found to be a substrate for the TcPDEB1 catalytic domain, opening the possibility of using this molecule as a substrate in non-radioactive, fluorescence-based PDE assays, including screening for trypanosome PDE inhibitors.

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Bowman, Amber L., Dawn H. Catino, John C. Strong, William R. Randall, Aikaterini Kontrogianni-Konstantopoulos, and Robert J. Bloch. "The Rho-Guanine Nucleotide Exchange Factor Domain of Obscurin Regulates Assembly of Titin at the Z-Disk through Interactions with Ran Binding Protein 9." Molecular Biology of the Cell 19, no. 9 (September 2008): 3782–92. http://dx.doi.org/10.1091/mbc.e08-03-0237.

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Obscurin is an ∼800-kDa protein composed of structural and signaling domains that organizes contractile structures in striated muscle. We have studied the Rho-GEF domain of obscurin to understand its roles in morphogenesis and signaling. We used adenoviral overexpression of this domain, together with ultrastructural and immunofluorescence methods, to examine its effect on maturing myofibrils. We report that overexpression of the Rho-GEF domain specifically inhibits the incorporation of titin into developing Z-disks and disrupts the structure of the Z-disk and Z/I junction, and alters features of the A/I junction. The organization of other sarcomeric markers, including α-actinin, was not affected. We identified Ran binding protein 9 (RanBP9) as a novel ligand of the Rho-GEF domain and showed that binding is specific, with an apparent binding affinity of 1.9 μM. Overexpression of the binding region of RanBP9 also disrupted the incorporation of titin into developing Z-disks. Immunofluorescence localization during myofibrillogenesis indicated that the Rho-GEF domain assembles into sarcomeres before RanBP9, which first occurs in myonuclei and later in development translocates to the myoplasm, where it colocalizes with obscurin. Both the Rho-GEF domain and its binding region on RanBP9 bind directly to the N-terminal Ig domains of titin, which flank the Z-disk. Our results suggest that the Rho-GEF domain interacts with RanBP9 and that both can interact with the N-terminal region of titin to influence the formation of the Z-disk and A/I junction.

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Meller, Nahum, M. Jody Westbrook, John D. Shannon, Chittibabu Guda, and Martin A. Schwartz. "Function of the N-terminus of zizimin1: autoinhibition and membrane targeting." Biochemical Journal 409, no. 2 (December 21, 2007): 525–33. http://dx.doi.org/10.1042/bj20071263.

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Rho family small GTPases are critical regulators of multiple cellular functions. Dbl-homology-domain-containing proteins are the classical GEFs (guanine nucleotide exchange factors) responsible for activation of Rho proteins. Zizimin1 is a Cdc42-specific GEF that belongs to a second family of mammalian Rho-GEFs, CZH [CDM (Ced-5/DOCK180/Myoblast city)-zizimin homology] proteins, which possess a novel type of GEF domain. CZH proteins can be divided into a subfamily related to DOCK 180 and a subfamily related to zizimin1. The two groups share two conserved regions named the CZH1 (or DHR1) domain and the CZH2 (DHR2 or DOCKER) domains, the latter exhibiting GEF activity. We now show that limited proteolysis of zizimin1 suggests the existence of structural domains that do not correspond to those identified on the basis of homologies. We demonstrate that the N-terminal half binds to the GEF domain through three distinct areas, including the CZH1, to inhibit the interaction with Cdc42. The N-terminal PH (pleckstrin homology) domain binds phosphoinositides and mediates zizimin1 membrane targeting. These results define two novel functions for the N-terminal region of zizimin1.

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Rodriguez, Alyssa A., Jessica L. Wojtaszek, Briana H. Greer, Tuhin Haldar, Kent S. Gates, R. Scott Williams, and Brandt F. Eichman. "An autoinhibitory role for the GRF zinc finger domain of DNA glycosylase NEIL3." Journal of Biological Chemistry 295, no. 46 (September 2, 2020): 15566–75. http://dx.doi.org/10.1074/jbc.ra120.015541.

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The NEIL3 DNA glycosylase maintains genome integrity during replication by excising oxidized bases from single-stranded DNA (ssDNA) and unhooking interstrand cross-links (ICLs) at fork structures. In addition to its N-terminal catalytic glycosylase domain, NEIL3 contains two tandem C-terminal GRF-type zinc fingers that are absent in the other NEIL paralogs. ssDNA binding by the GRF–ZF motifs helps recruit NEIL3 to replication forks converged at an ICL, but the nature of DNA binding and the effect of the GRF–ZF domain on catalysis of base excision and ICL unhooking is unknown. Here, we show that the tandem GRF–ZFs of NEIL3 provide affinity and specificity for DNA that is greater than each individual motif alone. The crystal structure of the GRF domain shows that the tandem ZF motifs adopt a flexible head-to-tail configuration well-suited for binding to multiple ssDNA conformations. Functionally, we establish that the NEIL3 GRF domain inhibits glycosylase activity against monoadducts and ICLs. This autoinhibitory activity contrasts GRF–ZF domains of other DNA-processing enzymes, which typically use ssDNA binding to enhance catalytic activity, and suggests that the C-terminal region of NEIL3 is involved in both DNA damage recruitment and enzymatic regulation.

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Perrin, Marilyn H., Steve Sutton, Deborah L. Bain, W. Travis Berggren, and Wylie W. Vale. "The First Extracellular Domain of Corticotropin Releasing Factor-R1 Contains Major Binding Determinants for Urocortin and Astressin*." Endocrinology 139, no. 2 (February 1, 1998): 566–70. http://dx.doi.org/10.1210/endo.139.2.5757.

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Abstract The CRF receptors are members of a 7-transmembrane receptor family that includes GH-releasing hormone (GRF), calcitonin, vasoactive intestinal peptide (VIP), secretin, and PTH receptors. To determine the structural features of the CRF receptor that may influence ligand recognition, a series of mutant receptors was analyzed for binding to astressin, a CRF antagonist, and to urocortin, a CRF agonist. Mutant receptors included chimeras between the CRF-R1 and GRF-R or Activin IIB-R, a single membrane spanning receptor serine/threonine kinase. Binding to the mutant receptors was assessed using 125I-[DTyr1] astressin (Ast*) and 125I-[Tyr0]-rat urocortin (Ucn*). There was no binding to a chimeric receptor in which the first extracellular domain (E1c) (i.e. the N-terminal region) of the CRF-R1 was replaced by that of the GRF-R. The complementary chimera in which E1 domain of the GRF-R was replaced by that of the CRF-R1 bound astressin and urocortin with Ki values approximately 10 nm, compared with inhibitory binding dissociation constant (Ki) values of approximately 2–4 nm for the wild-type CRF-R1. The chimera in which E1 of the activin IIB receptor was replaced by E1 of the CRF-R1 bound astressin with a Ki approximately 4 nm. A chimera in which both the first and fourth extracellular domains of the CRF-R1 replaced the corresponding domains of the GRF-R bound astressin with Ki approximately 4 nm and urocortin with a Ki approximately 2 nm. A chimera in which all four extracellular domains of the CRF receptor replaced those of the GRF-R bound astressin and urocortin with Ki values approximately 4 nm and approximately 1 nm, respectively. In conclusion, the major determinants for high affinity binding of CRF agonists and antagonists to CRF-R1 are found in the first extracellular domain of the receptor.

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Kalesnikoff, Janet, Eon J. Rios, Ching-Cheng Chen, M. Alejandro Barbieri, Mindy Tsai, See-Ying Tam, and Stephen J. Galli. "Roles of RabGEF1/Rabex-5 domains in regulating FcϵRI surface expression and FcϵRI-dependent responses in mast cells." Blood 109, no. 12 (June 15, 2007): 5308–17. http://dx.doi.org/10.1182/blood-2007-01-067363.

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Abstract RabGEF1/Rabex-5, a guanine nucleotide exchange factor (GEF) for the endocytic pathway regulator, Rab5, contains a Vps9 domain, an A20-like zinc finger (ZnF) domain, and a coiled coil domain. To investigate the importance of these domains in regulating receptor internalization and cell activation, we lentivirally delivered RabGEF1 mutants into RabGEF1-deficient (−/−) mast cells and examined FcϵRI-dependent responses. Wild-type RabGEF1 expression corrected phenotypic abnormalities in −/− mast cells, including decreased basal FcϵRI expression, slowed FcϵRI internalization, elevated IgE + Ag–induced degranulation and IL-6 production, and the decreased ability of −/− cytosol to support endosome fusion. We showed that RabGEF1's ZnF domain has ubiquitin ligase activity. Moreover, the coiled coil domain of RabGEF1 is required for Rabaptin-5 binding and for maintaining basal levels of Rabaptin-5 and surface FcϵRI. However, mutants lacking either of these domains normalized phenotypic abnormalities in IgE + antigen–activated −/− mast cells. By contrast, correction of these −/− phenotypes required a functional Vps9 domain. Thus, FcϵRI-mediated mast cell functional activation is dependent on RabGEF1's GEF activity.

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Nakashima, Kosuke, and Hideki Matsui. "A Novel Inhibition Modality for Phosphodiesterase 2A." SLAS DISCOVERY: Advancing the Science of Drug Discovery 25, no. 5 (April 28, 2020): 498–505. http://dx.doi.org/10.1177/2472555220913241.

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Phosphodiesterase type 2A (PDE2A) has received considerable interest as a molecular target for treating central nervous system diseases that affect memory, learning, and cognition. In this paper, the authors present the discovery of small molecules that have a novel modality of PDE2A inhibition. PDE2A possesses GAF-A and GAF-B domains and is a dual-substrate enzyme capable of hydrolyzing both cGMP and cAMP, and activation occurs through cGMP binding to the GAF-B domain. Thus, positive feedback of the catalytic activity to hydrolyze cyclic nucleotides occurs in the presence of appropriate concentrations of cGMP, which binds to the GAF-B domain, resulting in a “brake” that attenuates downstream cyclic nucleotide signaling. Here, we studied the inhibitory effects of some previously reported PDE2A inhibitors, all of which showed impaired inhibitory effects at a lower concentration of cGMP (70 nM) than a concentration effective for the positive feedback (4 μM). This impairment depended on the presence of the GAF domains but was not attributed to binding of the inhibitors to these domains. Notably, we identified PDE2A inhibitors that did not exhibit this behavior; that is, the inhibitory effects of these inhibitors were as strong at the lower concentration of cGMP (70 nM) as they were at the higher concentration (4 μM). This suggests that such inhibitors are likely to be more effective than previously reported PDE2A inhibitors in tissues of patients with lower cGMP concentrations.

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Baumeister, Mark A., Kent L. Rossman, John Sondek, and Mark A. Lemmon. "The Dbs PH domain contributes independently to membrane targeting and regulation of guanine nucleotide-exchange activity." Biochemical Journal 400, no. 3 (November 28, 2006): 563–72. http://dx.doi.org/10.1042/bj20061020.

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Dbl family GEFs (guanine nucleotide-exchange factors) for the Rho GTPases almost invariably contain a PH (pleckstrin homology) domain adjacent to their DH (Dbl homology) domain. The DH domain is responsible for GEF activity, and the PH domain plays a regulatory role that remains poorly understood. We demonstrated previously that Dbl family PH domains bind phosphoinositides with low affinity and cannot function as independent membrane targeting modules. In the present study, we show that dimerization of a Dbs (Dbl's big sister) DH/PH domain fragment is sufficient to drive it to the plasma membrane through a mechanism involving PH domain–phosphoinositide interactions. Thus, the Dbs PH domain could play a significant role in membrane targeting if it co-operates with other domains in the protein. We also show that mutations that prevent phosphoinositide binding by the Dbs PH domain significantly impair cellular GEF activity even in chimaeric proteins that are robustly membrane targeted by farnesylation or by the PH domain of phospholipase C-δ1. This finding argues that the Dbs PH domain plays a regulatory role that is independent of its ability to aid membrane targeting. Thus, we suggest that the PH domain plays dual roles, contributing independently to membrane localization of Dbs (as part of a multi-domain interaction) and allosteric regulation of the DH domain.

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Lim, Christopher, Jason M. Berk, Alyssa Blaise, Josie Bircher, Anthony J. Koleske, Mark Hochstrasser, and Yong Xiong. "Crystal structure of a guanine nucleotide exchange factor encoded by the scrub typhus pathogenOrientia tsutsugamushi." Proceedings of the National Academy of Sciences 117, no. 48 (November 12, 2020): 30380–90. http://dx.doi.org/10.1073/pnas.2018163117.

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Rho family GTPases regulate an array of cellular processes and are often modulated by pathogens to promote infection. Here, we identify a cryptic guanine nucleotide exchange factor (GEF) domain in the OtDUB protein encoded by the pathogenic bacteriumOrientia tsutsugamushi. A proteomics-based OtDUB interaction screen identified numerous potential host interactors, including the Rho GTPases Rac1 and Cdc42. We discovered a domain in OtDUB with Rac1/Cdc42 GEF activity (OtDUBGEF), with higher activity toward Rac1 in vitro. While this GEF bears no obvious sequence similarity to known GEFs, crystal structures of OtDUBGEFalone (3.0 Å) and complexed with Rac1 (1.7 Å) reveal striking convergent evolution, with a unique topology, on a V-shaped bacterial GEF fold shared with other bacterial GEF domains. Structure-guided mutational analyses identified residues critical for activity and a mechanism for nucleotide displacement. Ectopic expression of OtDUB activates Rac1 preferentially in cells, and expression of the OtDUBGEFalone alters cell morphology. Cumulatively, this work reveals a bacterial GEF within the multifunctional OtDUB that co-opts host Rac1 signaling to induce changes in cytoskeletal structure.

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Wallace, Bret D., Zachary Berman, Geoffrey A. Mueller, Yunfeng Lin, Timothy Chang, Sara N. Andres, Jessica L. Wojtaszek, et al. "APE2 Zf-GRF facilitates 3′-5′ resection of DNA damage following oxidative stress." Proceedings of the National Academy of Sciences 114, no. 2 (December 27, 2016): 304–9. http://dx.doi.org/10.1073/pnas.1610011114.

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The Xenopus laevis APE2 (apurinic/apyrimidinic endonuclease 2) nuclease participates in 3′-5′ nucleolytic resection of oxidative DNA damage and activation of the ATR-Chk1 DNA damage response (DDR) pathway via ill-defined mechanisms. Here we report that APE2 resection activity is regulated by DNA interactions in its Zf-GRF domain, a region sharing high homology with DDR proteins Topoisomerase 3α (TOP3α) and NEIL3 (Nei-like DNA glycosylase 3), as well as transcription and RNA regulatory proteins, such as TTF2 (transcription termination factor 2), TFIIS, and RPB9. Biochemical and NMR results establish the nucleic acid-binding activity of the Zf-GRF domain. Moreover, an APE2 Zf-GRF X-ray structure and small-angle X-ray scattering analyses show that the Zf-GRF fold is typified by a crescent-shaped ssDNA binding claw that is flexibly appended to an APE2 endonuclease/exonuclease/phosphatase (EEP) catalytic core. Structure-guided Zf-GRF mutations impact APE2 DNA binding and 3′-5′ exonuclease processing, and also prevent efficient APE2-dependent RPA recruitment to damaged chromatin and activation of the ATR-Chk1 DDR pathway in response to oxidative stress in Xenopus egg extracts. Collectively, our data unveil the APE2 Zf-GRF domain as a nucleic acid interaction module in the regulation of a key single-strand break resection function of APE2, and also reveal topologic similarity of the Zf-GRF to the zinc ribbon domains of TFIIS and RPB9.

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Stepanenko, Olga V., Irina M. Kuznetsova, Konstantin K. Turoverov, and Olesya V. Stepanenko. "Impact of Double Covalent Binding of BV in NIR FPs on Their Spectral and Physicochemical Properties." International Journal of Molecular Sciences 23, no. 13 (July 1, 2022): 7347. http://dx.doi.org/10.3390/ijms23137347.

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Understanding the photophysical properties and stability of near-infrared fluorescent proteins (NIR FPs) based on bacterial phytochromes is of great importance for the design of efficient fluorescent probes for use in cells and in vivo. Previously, the natural ligand of NIR FPs biliverdin (BV) has been revealed to be capable of covalent binding to the inherent cysteine residue in the PAS domain (Cys15), and to the cysteine residue introduced into the GAF domain (Cys256), as well as simultaneously with these two residues. Here, based on the spectroscopic analysis of several NIR FPs with both cysteine residues in PAS and GAF domains, we show that the covalent binding of BV simultaneously with two domains is the reason for the higher quantum yield of BV fluorescence in these proteins as a result of rigid fixation of the chromophore in their chromophore-binding pocket. We demonstrate that since the attachment sites are located in different regions of the polypeptide chain forming a figure-of-eight knot, their binding to BV leads to shielding of many sites of proteolytic degradation due to additional stabilization of the entire protein structure. This makes NIR FPs with both cysteine residues in PAS and GAF domains less susceptible to cleavage by intracellular proteases.

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Mishra, Vishnu Narayan, and Garima Tomar. "Existence of wandering and periodic domain in given angular region." Mathematica Slovaca 70, no. 4 (August 26, 2020): 839–48. http://dx.doi.org/10.1515/ms-2017-0397.

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AbstractDynamics of composition of entire functions is well related to it's factors, as it is known that for entire functions f and g, fog has wandering domain if and only if gof has wandering domain. However the Fatou components may have different structures and properties. In this paper we have shown the existence of domains with all possibilities of wandering and periodic in given angular region θ.

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Wang, Yi-Chun, Shang-Hsuan Huang, Chien-Ping Chang, and Chuan Li. "Identification and Characterization of Glycine- and Arginine-Rich Motifs in Proteins by a Novel GAR Motif Finder Program." Genes 14, no. 2 (January 27, 2023): 330. http://dx.doi.org/10.3390/genes14020330.

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Glycine- and arginine-rich (GAR) motifs with different combinations of RG/RGG repeats are present in many proteins. The nucleolar rRNA 2′-O-methyltransferase fibrillarin (FBL) contains a conserved long N-terminal GAR domain with more than 10 RGG plus RG repeats separated by specific amino acids, mostly phenylanalines. We developed a GAR motif finder (GMF) program based on the features of the GAR domain of FBL. The G(0,3)-X(0,1)-R-G(1,2)-X(0,5)-G(0,2)-X(0,1)-R-G(1,2) pattern allows the accommodation of extra-long GAR motifs with continuous RG/RGG interrupted by polyglycine or other amino acids. The program has a graphic interface and can easily output the results as .csv and .txt files. We used GMF to show the characteristics of the long GAR domains in FBL and two other nucleolar proteins, nucleolin and GAR1. GMF analyses can illustrate the similarities and also differences between the long GAR domains in the three nucleolar proteins and motifs in other typical RG/RGG-repeat-containing proteins, specifically the FET family members FUS, EWS, and TAF15 in position, motif length, RG/RGG number, and amino acid composition. We also used GMF to analyze the human proteome and focused on the ones with at least 10 RGG plus RG repeats. We showed the classification of the long GAR motifs and their putative correlation with protein/RNA interactions and liquid–liquid phase separation. The GMF algorithm can facilitate further systematic analyses of the GAR motifs in proteins and proteomes.

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Schormann, Norbert, Manisha Patel, Luke Thannickal, Sangeetha Purushotham, Ren Wu, Joshua L. Mieher, Hui Wu, and Champion Deivanayagam. "The catalytic domains of Streptococcus mutans glucosyltransferases: a structural analysis." Acta Crystallographica Section F Structural Biology Communications 79, no. 5 (May 1, 2023): 119–27. http://dx.doi.org/10.1107/s2053230x23003199.

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Streptococcus mutans, found in the human oral cavity, is a significant contributor to the pathogenesis of dental caries. This bacterium expresses three genetically distinct types of glucosyltransferases named GtfB (GTF-I), GtfC (GTF-SI) and GtfD (GTF-S) that play critical roles in the development of dental plaque. The catalytic domains of GtfB, GtfC and GtfD contain conserved active-site residues for the overall enzymatic activity that relate to hydrolytic glycosidic cleavage of sucrose to glucose and fructose, release of fructose and generation of a glycosyl-enzyme intermediate in the reducing end. In a subsequent transglycosylation step, the glucosyl moiety is transferred to the nonreducing end of an acceptor to form a growing glucan polymer chain made up of glucose molecules. It has been proposed that both sucrose breakdown and glucan synthesis occur in the same active site of the catalytic domain, although the active site does not appear to be large enough to accommodate both functions. These three enzymes belong to glycoside hydrolase family 70 (GH70), which shows homology to glycoside hydrolase family 13 (GH13). GtfC synthesizes both soluble and insoluble glucans (α-1,3 and α-1,6 glycosidic linkages), while GtfB and GtfD synthesize only insoluble or soluble glucans, respectively. Here, crystal structures of the catalytic domains of GtfB and GtfD are reported. These structures are compared with previously determined structures of the catalytic domain of GtfC. With this work, apo structures and inhibitor-complex structures with acarbose are now available for the catalytic domains of GtfC and GtfB. The structure of GtfC with maltose allows further identification and comparison of active-site residues. A model of sucrose binding to GtfB is also included. The new structure of the catalytic domain of GtfD affords a structural comparison of the three S. mutans glycosyltransferases. Unfortunately, the catalytic domain of GtfD is not complete since crystallization resulted in the structure of a truncated protein lacking approximately 200 N-terminal residues of domain IV.

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Firestein, Ron, and Michael L. Cleary. "Pseudo-phosphatase Sbf1 contains an N-terminal GEF homology domain that modulates its growth regulatory properties." Journal of Cell Science 114, no. 16 (August 15, 2001): 2921–27. http://dx.doi.org/10.1242/jcs.114.16.2921.

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Sbf1 (SET binding factor 1) is a pseudo-phosphatase related to the myotubularin family of dual specificity phosphatases, some of which have been implicated in cellular growth and differentiation by virtue of their mutation in human genetic disorders. Sbf1 contains germline-encoded alterations of its myotubularin homology domain that render it non-functional as a phosphatase. We report here the complete structure of Sbf1 and further characterization of its growth regulatory properties. In addition to its similarity to myotubularin, the predicted full-length Sbf1 protein contains pleckstrin (PH)and GEF homology domains that are conserved in several proteins implicated in signaling and growth control. Forced expression of wild-type Sbf1 in NIH 3T3 cells inhibited their proliferation and altered their morphology. These effects required intact PH, GEF and myotubularin homology domains, implying that growth inhibition may be an intrinsic property of wild-type Sbf1. Conversely, deletion of its conserved N-terminal 44 amino acids alone was sufficient to convert Sbf1 from an inhibitor of cellular growth to a transforming protein in NIH 3T3 cells. Oncogenic forms of Sbf1 partially localized to the nucleus, in contrast to the exclusively cytoplasmic subcellular localization of endogenous Sbf1 in all cell lines and mammalian tissues tested. These data show that the N-terminal GEF homology domain serves to inhibit the transforming effects of Sbf1, possibly sequestering the protein to the cytoplasm, and suggest that this region may be a modulatory domain that relays growth control signals.

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Xu, Qian-Zhao, Pavlo Bielytskyi, James Otis, Christina Lang, Jon Hughes, Kai-Hong Zhao, Aba Losi, Wolfgang Gärtner, and Chen Song. "MAS NMR on a Red/Far-Red Photochromic Cyanobacteriochrome All2699 from Nostoc." International Journal of Molecular Sciences 20, no. 15 (July 26, 2019): 3656. http://dx.doi.org/10.3390/ijms20153656.

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Unlike canonical phytochromes, the GAF domain of cyanobacteriochromes (CBCRs) can bind bilins autonomously and is sufficient for functional photocycles. Despite the astonishing spectral diversity of CBCRs, the GAF1 domain of the three-GAF-domain photoreceptor all2699 from the cyanobacterium Nostoc 7120 is the only CBCR-GAF known that converts from a red-absorbing (Pr) dark state to a far-red-absorbing (Pfr) photoproduct, analogous to the more conservative phytochromes. Here we report a solid-state NMR spectroscopic study of all2699g1 in its Pr state. Conclusive NMR evidence unveils a particular stereochemical heterogeneity at the tetrahedral C31 atom, whereas the crystal structure shows exclusively the R-stereochemistry at this chiral center. Additional NMR experiments were performed on a construct comprising the GAF1 and GAF2 domains of all2699, showing a greater precision in the chromophore–protein interactions in the GAF1-2 construct. A 3D Pr structural model of the all2699g1-2 construct predicts a tongue-like region extending from the GAF2 domain (akin to canonical phytochromes) in the direction of the chromophore, shielding it from the solvent. In addition, this stabilizing element allows exclusively the R-stereochemistry for the chromophore-protein linkage. Site-directed mutagenesis performed on three conserved motifs in the hairpin-like tip confirms the interaction of the tongue region with the GAF1-bound chromophore.

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Mizoguchi, Yoko, Miyuki Tsumura, Satoshi Okada, Osamu Hirata, Shizuko Minegishi, Nobuyuki Hyakuna, Jean-Laurent Casanova, Tomohiro Morio, and Masao Kobayashi. "STAT1 Gain-of-Function in Patients with Chronic Mucocutaneous Candidiasis Can be Detected By the Excessive Phosphorylation of STAT1 in Peripheral Blood Monocytes." Blood 124, no. 21 (December 6, 2014): 4111. http://dx.doi.org/10.1182/blood.v124.21.4111.4111.

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Abstract Chronic mucocutaneous candidiasis (CMCD) is a rare congenital disorder characterized by persistent or recurrent skin, nails and mucosal membranes infections caused by Candida albicans. Several studies suggest that impairment of development in Th17 linage and/or IL-17 signaling could be responsible for development of CMCD and seven responsible genes, CARD9, STAT3, IL12B, IL12RB1, IL17RA, IL17F, and AIRE have been identified. Recently, heterozygous mutations in coiled-coil domain (CCD) and DNA-binding domain (DBD) of STAT1 are identified in approximately 40% of patients with CMCD. Signal transducer and activation of transcription 1 (STAT1) is a DNA-binding factor which regulates specific gene transcription. STAT1 mutations identified in patients with CMCD are gain-of-function (GOF), gain-of-gamma-activated factor (GAF) DNA binding and gain-of-gamma-activated sequence (GAS) transcription activity in response to IFN-γ, IFN-α and IL-27. Based on the results of transient gene experiments, impairment in dephosphorylation of STAT1 has been considered to be a molecular pathogenesis underlying the increased phosphorylation of STAT1 at Tyr701 (pSTAT1). In this paper, we aimed to identify and characterize STAT1 mutations in CMCD patients, and to develop a simple diagnostic assay of CMCD. Five sporadic and five familial cases of CMCD, from a total of 15 patients from 10 kindreds in Japan, are investigated. Six heterozygous missense mutations, including three novel mutations, in CCD and DBD of STAT1 were identified in two sporadic and four familial cases in 10 patients with CMCD. Thus, STAT1 mutations were commonly identified in Japanese patients with CMCD. We investigated functional significance of these mutations by transient gene expression experiments using U3C STAT1 null fibrosarcoma cells. Similar to the previous studies, all mutant proteins showed increased pSTAT1 in response to IFN-α and IFN-γ. Increased GAF-DNA binding and GAS transcription activity were observed in mutant expressed cells. Thus, these mutations are GOF mutations against GAF mediated transcription activity. Next, we studied dephosphorylation of STAT1 using peripheral blood mononuclear cell (PBMCs) from the patients. As the STAT1 GOF mutations are thought to be associated with impairment in dephosphorylation of STAT1, we used staurosporine, the tyrosine kinase inhibitor which inhibits JAK-STAT signaling upstream of STAT1, to clarify the difference between STAT1 WT alleles and STAT1 GOF alleles. If the STAT1 dephosphorylation normally occurs in the nucleus, pSTAT1 should promptly decrease following staurosporine treatment. PBMCs from fourteen healthy individuals and ten patients with CMCD carrying GOF STAT1 mutations were incubated with staurosporine followed by IFN-γ stimulation and analyzed by flow cytometry. Some overlap was observed, but MFI values for pSTAT1 in response to IFN-γ were significantly higher in CD14+ cells from the patients than in those from the controls PBMCs from the patients. This excess phosphorylation persisted after 15 minutes of treatment with staurosporine. Moreover, in these conditions, there was no overlap in MFI of pSTAT1 between the patients and healthy controls. These findings suggest that excess pSTAT1 is caused by an impairment of dephosphorylation and this flow cytometry-based technique is likely to be useful for the rapid assessment of STAT1 function in CMCD patients. Disclosures No relevant conflicts of interest to declare.

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ERCAN, Altan. "Sex effect on the correlation of immunoglobulin G glycosylation with rheumatoid arthritis disease activity." TURKISH JOURNAL OF BIOLOGY 44, no. 6 (December 14, 2020): 406–16. http://dx.doi.org/10.3906/biy-2005-7.

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Rheumatoid arthritis (RA) is a chronic autoimmune disease which affects females more than males with a presence of auto-antibodies. Immunoglobulin G (IgG) produced by adaptive arm has 2 functional domains, Fc and Fab. The Fc domain binds Fc gamma receptors and C1q proteins of the innate arm. Therefore, the IgG Fc domain serves as a bridge between the innate and adaptive arms and is regulated by an evolutionarily conserved N-glycosylation with variable structures. These glycans are classified as agalactosylated G0, monogalactosylated G1, and digalactosylated G2, which are further modified by core-fucosylation (F) and bisecting N-acetylglu-cosamine (B) moieties such as G0F and G0FB. Interestingly, proinflammatory G0F is shown to be regulated by estrogen in vivo. Here, it is hypothesized that the regulation of G0F by estrogen contributes to sex dichotomy in RA by setting up the level of IgG-dependent inflammation and therefore, RA disease activity (Das28-CRP3). To investigate this hypothesis, IgG glycosylation was characterized in serum samples from active RA patients (n = 232) and healthy controls (n = 232) by serum N-glycan analysis using the high performance liquid chromatography. According to the results, the IgG Fc glycan phenotype originates predominantly from the structure of G0F, and both G0F and G0FB correlate with Das28-CRP3 in females, but not in males. In conclusion, IgG G0F-dependent inflammation differs in males and females, and these differences point to the differential regulation of inflammation by sex hormone estrogen via IgG gly-cosylation.

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Schultz, Joachim E., Sandra Bruder, Anita Schultz, Sergio E. Martinez, Ning Zheng, and Joseph A. Beavo. "Bacterial GAF domains." BMC Pharmacology 5, Suppl 1 (2005): S17. http://dx.doi.org/10.1186/1471-2210-5-s1-s17.

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Galperin, Michael Y. "Structural Classification of Bacterial Response Regulators: Diversity of Output Domains and Domain Combinations." Journal of Bacteriology 188, no. 12 (June 15, 2006): 4169–82. http://dx.doi.org/10.1128/jb.01887-05.

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ABSTRACT CheY-like phosphoacceptor (or receiver [REC]) domain is a common module in a variety of response regulators of the bacterial signal transduction systems. In this work, 4,610 response regulators, encoded in complete genomes of 200 bacterial and archaeal species, were identified and classified by their domain architectures. Previously uncharacterized output domains were analyzed and, in some cases, assigned to known domain families. Transcriptional regulators of the OmpR, NarL, and NtrC families were found to comprise almost 60% of all response regulators; transcriptional regulators with other DNA-binding domains (LytTR, AraC, Spo0A, Fis, YcbB, RpoE, and MerR) account for an additional 6%. The remaining one-third is represented by the stand-alone REC domain (∼14%) and its combinations with a variety of enzymatic (GGDEF, EAL, HD-GYP, CheB, CheC, PP2C, and HisK), RNA-binding (ANTAR and CsrA), protein- or ligand-binding (PAS, GAF, TPR, CAP_ED, and HPt) domains, or newly described domains of unknown function. The diversity of domain architectures and the abundance of alternative domain combinations suggest that fusions between the REC domain and various output domains is a widespread evolutionary mechanism that allows bacterial cells to regulate transcription, enzyme activity, and/or protein-protein interactions in response to environmental challenges. The complete list of response regulators encoded in each of the 200 analyzed genomes is available online at http://www.ncbi.nlm.nih.gov/Complete_Genomes/RRcensus.html .

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Lee, Jin-Mok, Ha Yeon Cho, Hyo Je Cho, In-Jeong Ko, Sae Woong Park, Hyung-Suk Baik, Jee-Hyun Oh, et al. "O2- and NO-Sensing Mechanism through the DevSR Two-Component System in Mycobacterium smegmatis." Journal of Bacteriology 190, no. 20 (August 15, 2008): 6795–804. http://dx.doi.org/10.1128/jb.00401-08.

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ABSTRACT The DevS histidine kinase of Mycobacterium smegmatis contains tandem GAF domains (GAF-A and GAF-B) in its N-terminal sensory domain. The heme iron of DevS is in the ferrous state when purified and is resistant to autooxidation from a ferrous to a ferric state in the presence of O2. The redox property of the heme and the results of sequence comparison analysis indicate that DevS of M. smegmatis is more closely related to DosT of Mycobacterium tuberculosis than DevS of M. tuberculosis. The binding of O2 to the deoxyferrous heme led to a decrease in the autokinase activity of DevS, whereas NO binding did not. The regulation of DevS autokinase activity in response to O2 and NO was not observed in the DevS derivatives lacking its heme, indicating that the ligand-binding state of the heme plays an important role in the regulation of DevS kinase activity. The redox state of the quinone/quinol pool of the respiratory electron transport chain appears not to be implicated in the regulation of DevS activity. Neither cyclic GMP (cGMP) nor cAMP affected DevS autokinase activity, excluding the possibility that the cyclic nucleotides serve as the effector molecules to modulate DevS kinase activity. The three-dimensional structure of the putative GAF-B domain revealed that it has a GAF folding structure without cyclic nucleotide binding capacity.

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Blangy, A., E. Vignal, S. Schmidt, A. Debant, C. Gauthier-Rouviere, and P. Fort. "TrioGEF1 controls Rac- and Cdc42-dependent cell structures through the direct activation of rhoG." Journal of Cell Science 113, no. 4 (February 15, 2000): 729–39. http://dx.doi.org/10.1242/jcs.113.4.729.

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Rho GTPases regulate the morphology of cells stimulated by extracellular ligands. Their activation is controlled by guanine exchange factors (GEF) that catalyze their binding to GTP. The multidomain Trio protein represents an emerging class of Ρ regulators that contain two GEF domains of distinct specificities. We report here the characterization of Rho signaling pathways activated by the N-terminal GEF domain of Trio (TrioD1). In fibroblasts, TrioD1 triggers the formation of particular cell structures, similar to those elicited by RhoG, a GTPase known to activate both Rac1 and Cdc42Hs. In addition, the activity of TrioD1 requires the microtubule network and relocalizes RhoG at the active sites of the plasma membrane. Using a classical in vitro exchange assay, TrioD1 displays a higher GEF activity on RhoG than on Rac1. In fibroblasts, expression of dominant negative RhoG mutants totally abolished TrioD1 signaling, whereas dominant negative Rac1 and Cdc42Hs only led to partial and complementary inhibitions. Finally, expression of a Rho Binding Domain that specifically binds RhoG(GTP) led to the complete abolition of TrioD1 signaling, which strongly supports Rac1 not being activated by TrioD1 in vivo. These data demonstrate that Trio controls a signaling cascade that activates RhoG, which in turn activates Rac1 and Cdc42Hs.

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Marlaire, Simon, and Christoph Dehio. "Bartonella effector protein C mediates actin stress fiber formation via recruitment of GEF-H1 to the plasma membrane." PLOS Pathogens 17, no. 1 (January 28, 2021): e1008548. http://dx.doi.org/10.1371/journal.ppat.1008548.

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Bartonellae are Gram-negative facultative-intracellular pathogens that use a type-IV-secretion system (T4SS) to translocate a cocktail of Bartonella effector proteins (Beps) into host cells to modulate diverse cellular functions. BepC was initially reported to act in concert with BepF in triggering major actin cytoskeletal rearrangements that result in the internalization of a large bacterial aggregate by the so-called ‘invasome’. Later, infection studies with bepC deletion mutants and ectopic expression of BepC have implicated this effector in triggering an actin-dependent cell contractility phenotype characterized by fragmentation of migrating cells due to deficient rear detachment at the trailing edge, and BepE was shown to counterbalance this remarkable phenotype. However, the molecular mechanism of how BepC triggers cytoskeletal changes and the host factors involved remained elusive. Using infection assays, we show here that T4SS-mediated transfer of BepC is sufficient to trigger stress fiber formation in non-migrating epithelial cells and additionally cell fragmentation in migrating endothelial cells. Interactomic analysis revealed binding of BepC to a complex of the Rho guanine nucleotide exchange factor GEF-H1 and the serine/threonine-protein kinase MRCKα. Knock-out cell lines revealed that only GEF-H1 is required for mediating BepC-triggered stress fiber formation and inhibitor studies implicated activation of the RhoA/ROCK pathway downstream of GEF-H1. Ectopic co-expression of tagged versions of GEF-H1 and BepC truncations revealed that the C-terminal ‘Bep intracellular delivery’ (BID) domain facilitated anchorage of BepC to the plasma membrane, whereas the N-terminal ‘filamentation induced by cAMP’ (FIC) domain facilitated binding of GEF-H1. While FIC domains typically mediate post-translational modifications, most prominently AMPylation, a mutant with quadruple amino acid exchanges in the putative active site indicated that the BepC FIC domain acts in a non-catalytic manner to activate GEF-H1. Our data support a model in which BepC activates the RhoA/ROCK pathway by re-localization of GEF-H1 from microtubules to the plasma membrane.

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Braga, Vania M. M. "GEF without a Dbl domain?" Nature Cell Biology 4, no. 8 (August 2002): E188—E190. http://dx.doi.org/10.1038/ncb0802-e188.

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Kajiho, Hiroaki, Kyoko Sakurai, Tomohiro Minoda, Manabu Yoshikawa, Satoshi Nakagawa, Shinichi Fukushima, Kenji Kontani, and Toshiaki Katada. "Characterization of RIN3 as a Guanine Nucleotide Exchange Factor for the Rab5 Subfamily GTPase Rab31." Journal of Biological Chemistry 286, no. 27 (May 17, 2011): 24364–73. http://dx.doi.org/10.1074/jbc.m110.172445.

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The small GTPase Rab5, which cycles between GDP-bound inactive and GTP-bound active forms, plays essential roles in membrane budding and trafficking in the early endocytic pathway. Rab5 is activated by various vacuolar protein sorting 9 (VPS9) domain-containing guanine nucleotide exchange factors. Rab21, Rab22, and Rab31 (members of the Rab5 subfamily) are also involved in the trafficking of early endosomes. Mechanisms controlling the activation Rab5 subfamily members remain unclear. RIN (Ras and Rab interactor) represents a family of multifunctional proteins that have a VPS9 domain in addition to Src homology 2 (SH2) and Ras association domains. We investigated whether RIN family members act as guanine nucleotide exchange factors (GEFs) for the Rab5 subfamily on biochemical and cell morphological levels. RIN3 stimulated the formation of GTP-bound Rab31 in cell-free and in cell GEF activity assays. RIN3 also formed enlarged vesicles and tubular structures, where it colocalized with Rab31 in HeLa cells. In contrast, RIN3 did not exhibit any apparent effects on Rab21. We also found that serine to alanine substitutions in the sequences between SH2 and RIN family homology domain of RIN3 specifically abolished its GEF action on Rab31 but not Rab5. We examined whether RIN3 affects localization of the cation-dependent mannose 6-phosphate receptor (CD-MPR), which is transported between trans-Golgi network and endocytic compartments. We found that RIN3 partially translocates CD-MPR from the trans-Golgi network to peripheral vesicles and that this is dependent on its Rab31-GEF activity. These results indicate that RIN3 specifically acts as a GEF for Rab31.

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Wearing, Scott C., James E. Smeathers, and Stephen R. Urry. "Frequency-Domain Analysis Detects Previously Unidentified Changes in Ground Reaction Force with Visually Guided Foot Placement." Journal of Applied Biomechanics 19, no. 1 (February 2003): 71–78. http://dx.doi.org/10.1123/jab.19.1.71.

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Studies investigating the effect of targeting on gait have focused on the analysis of ground reaction force (GRF) within the time domain. Analysis within the frequency domain may be a more sensitive method for evaluating variations in GRF. The aim of the present study was to investigate the effect of visual targeting on GRF analyzed within the frequency domain. A within-subject repeated-measures design was used to measure the mediolateral, vertical, and antero-posterior components of the GRF of 11 healthy volunteers while walking at their own pace over a paper-covered walkway. A 30 × 24-cm target area was superimposed over a hidden Kistler force plate mounted at the midpoint of the walkway. GRF were recorded with and without the target and were analyzed within the frequency domain. Although visually guided foot placement has previously been undetected by traditional time-domain measures, targeting was found to significantly increase the frequency content of both the mediolateral (t10= -4.07,p <0.05) and antero-posterior (t10= -2.52,p <0.05) components of GRF. Consequently, it appears that frequency analysis is a more sensitive analytic technique for evaluating GRF. These findings have methodological implications for research in which GRF is used to characterize and assess anomalies in gait patterns.

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Matovina, Mihaela, Ana Tomašić Paić, Sanja Tomić, Hrvoje Brkić, Lucija Horvat, Lea Barbarić, Vedrana Filić, Marija Pinterić, Snježana Jurić, and Akmaral Kussayeva. "Identification of SH2 Domain-Containing Protein 3C as a Novel, Putative Interactor of Dipeptidyl Peptidase 3." International Journal of Molecular Sciences 24, no. 18 (September 16, 2023): 14178. http://dx.doi.org/10.3390/ijms241814178.

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Dipeptidyl peptidase 3 (DPP3) is a zinc-dependent exopeptidase with broad specificity for four to eight amino acid residue substrates. It has a role in the regulation of oxidative stress response NRF2–KEAP1 pathway through the interaction with KEAP1. We have conducted stable isotope labeling by amino acids in a cell culture coupled to mass spectrometry (SILAC-MS) interactome analysis of TRex HEK293T cells using DPP3 as bait and identified SH2 Domain-Containing Protein 3C (SH2D3C) as prey. SH2D3C is one of three members of a family of proteins that contain both the SH2 domain and a domain similar to guanine nucleotide exchange factor domains of Ras family GTPases (Ras GEF-like domain), named novel SH2-containing proteins (NSP). NSPs, including SH2D3C (NSP3), are adaptor proteins involved in the regulation of adhesion, migration, tissue organization, and immune response. We have shown that SH2D3C binds to DPP3 through its C-terminal Ras GEF-like domain, detected the colocalization of the proteins in living cells, and confirmed direct interaction in the cytosol and membrane ruffles. Computational analysis also confirmed the binding of the C-terminal domain of SH2D3C to DPP3, but the exact model could not be discerned. This is the first indication that DPP3 and SH2D3C are interacting partners, and further studies to elucidate the physiological significance of this interaction are on the way.

Journal articles on the topic 'GYF domain'

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