Journal articles: 'Residue conservation; Protein folding'

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de Haard, H. J., B. Kazemier, A. van der Bent, P. Oudshoorn, P. Boender, B. van Gemen, J. W. Arends, and H. R. Hoogenboom. "Absolute conservation of residue 6 of immunoglobulin heavy chain variable regions of class IIA is required for correct folding." Protein Engineering Design and Selection 11, no. 12 (December 1, 1998): 1267–76. http://dx.doi.org/10.1093/protein/11.12.1267.

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Liu, Xinsheng, Jing Li, Wanlin Guo, and Wei Wang. "A new method for quantifying residue conservation and its applications to the protein folding nucleus." Biochemical and Biophysical Research Communications 351, no. 4 (December 2006): 1031–36. http://dx.doi.org/10.1016/j.bbrc.2006.10.157.

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Sergel, Theresa A., Lori W. McGinnes, and Trudy G. Morrison. "Mutations in the Fusion Peptide and Adjacent Heptad Repeat Inhibit Folding or Activity of the Newcastle Disease Virus Fusion Protein." Journal of Virology 75, no. 17 (September 1, 2001): 7934–43. http://dx.doi.org/10.1128/jvi.75.17.7934-7943.2001.

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ABSTRACT Paramyxovirus fusion proteins have two heptad repeat domains, HR1 and HR2, which have been implicated in the fusion activity of the protein. Peptides with sequences from these two domains form a six-stranded coiled coil, with the HR1 sequences forming a central trimer (K. A. Baker, R. E. Dutch, R. A. Lamb, and T. S. Jardetzky, Mol. Cell 3:309–319, 1999; X. Zhao, M. Singh, V. N. Malashkevich, and P. S. Kim, Proc. Natl. Acad. Sci. USA 97:14172–14177, 2000). We have extended our previous mutational analysis of the HR1 domain of the Newcastle disease virus fusion protein, focusing on the role of the amino acids forming the hydrophobic core of the trimer, amino acids in the “a” and “d” positions of the helix from amino acids 123 to 182. Both conservative and nonconservative point mutations were characterized for their effects on synthesis, stability, proteolytic cleavage, and surface expression. Mutant proteins expressed on the cell surface were characterized for fusion activity by measuring syncytium formation, content mixing, and lipid mixing. We found that all mutations in the “a” position interfered with proteolytic cleavage and surface expression of the protein, implicating the HR1 domain in the folding of the F protein. However, mutation of five of seven “d” position residues had little or no effect on surface expression but, with one exception at residue 175, did interfere to various extents with the fusion activity of the protein. One of these “d” mutations, at position 154, interfered with proteolytic cleavage, while the rest of the mutants were cleaved normally. That most “d” position residues do affect fusion activity argues that a stable HR1 trimer is required for formation of the six-stranded coiled coil and, therefore, optimal fusion activity. That most of the “d” position mutations do not block folding suggests that formation of the core trimer may not be required for folding of the prefusion form of the protein. We also found that mutations within the fusion peptide, at residue 128, can interfere with folding of the protein, implicating this region in folding of the molecule. No characterized mutation enhanced fusion.

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Toofanny, Rudesh D., Sara Calhoun, Amanda L. Jonsson, and Valerie Daggett. "Shared unfolding pathways of unrelated immunoglobulin-like β-sandwich proteins." Protein Engineering, Design and Selection 32, no. 7 (July 2019): 331–45. http://dx.doi.org/10.1093/protein/gzz040.

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Abstract The Dynameomics project contains native state and unfolding simulations of 807 protein domains, where each domain is representative of a different metafold; these metafolds encompass ~97% of protein fold space. There is a long-standing question in structural biology as to whether proteins in the same fold family share the same folding/unfolding characteristics. Using molecular dynamics simulations from the Dynameomics project, we conducted a detailed study of protein unfolding/folding pathways for 5 protein domains from the immunoglobulin (Ig)-like β-sandwich metafold (the highest ranked metafold in our database). The domains have sequence similarities ranging from 4 to 15% and are all from different SCOP superfamilies, yet they share the same overall Ig-like topology. Despite having very different amino acid sequences, the dominant unfolding pathway is very similar for the 5 proteins, and the secondary structures that are peripheral to the aligned, shared core domain add variability to the unfolding pathway. Aligned residues in the core domain display consensus structure in the transition state primarily through conservation of hydrophobic positions. Commonalities in the obligate folding nucleus indicate that insights into the major events in the folding/unfolding of other domains from this metafold may be obtainable from unfolding simulations of a few representative proteins.

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Michnick, Stephen W., and Eugene Shakhnovich. "A strategy for detecting the conservation of folding-nucleus residues in protein superfamilies." Folding and Design 3, no. 4 (August 1998): 239–51. http://dx.doi.org/10.1016/s1359-0278(98)00035-2.

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Larson, Stefan M., Ingo Ruczinski, Alan R. Davidson, David Baker, and Kevin W. Plaxco. "Residues participating in the protein folding nucleus do not exhibit preferential evolutionary conservation." Journal of Molecular Biology 316, no. 2 (February 2002): 225–33. http://dx.doi.org/10.1006/jmbi.2001.5344.

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Jain, Rohit, Khaja Muneeruddin, Jeremy Anderson, Michael J. Harms, Scott A. Shaffer, and C. Robert Matthews. "A conserved folding nucleus sculpts the free energy landscape of bacterial and archaeal orthologs from a divergent TIM barrel family." Proceedings of the National Academy of Sciences 118, no. 17 (April 19, 2021): e2019571118. http://dx.doi.org/10.1073/pnas.2019571118.

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The amino acid sequences of proteins have evolved over billions of years, preserving their structures and functions while responding to evolutionary forces. Are there conserved sequence and structural elements that preserve the protein folding mechanisms? The functionally diverse and ancient (βα)1–8 TIM barrel motif may answer this question. We mapped the complex six-state folding free energy surface of a ∼3.6 billion y old, bacterial indole-3-glycerol phosphate synthase (IGPS) TIM barrel enzyme by equilibrium and kinetic hydrogen–deuterium exchange mass spectrometry (HDX-MS). HDX-MS on the intact protein reported exchange in the native basin and the presence of two thermodynamically distinct on- and off-pathway intermediates in slow but dynamic equilibrium with each other. Proteolysis revealed protection in a small (α1β2) and a large cluster (β5α5β6α6β7) and that these clusters form cores of stability in Ia and Ibp. The strongest protection in both states resides in β4α4 with the highest density of branched aliphatic side chain contacts in the folded structure. Similar correlations were observed previously for an evolutionarily distinct archaeal IGPS, emphasizing a key role for hydrophobicity in stabilizing common high-energy folding intermediates. A bioinformatics analysis of IGPS sequences from the three superkingdoms revealed an exceedingly high hydrophobicity and surprising α-helix propensity for β4, preceded by a highly conserved βα-hairpin clamp that links β3 and β4. The conservation of the folding mechanisms for archaeal and bacterial IGPS proteins reflects the conservation of key elements of sequence and structure that first appeared in the last universal common ancestor of these ancient proteins.

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Cagiada, Matteo, Kristoffer E. Johansson, Audrone Valanciute, Sofie V. Nielsen, Rasmus Hartmann-Petersen, Jun J. Yang, Douglas M. Fowler, Amelie Stein, and Kresten Lindorff-Larsen. "Understanding the Origins of Loss of Protein Function by Analyzing the Effects of Thousands of Variants on Activity and Abundance." Molecular Biology and Evolution 38, no. 8 (March 29, 2021): 3235–46. http://dx.doi.org/10.1093/molbev/msab095.

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Abstract Understanding and predicting how amino acid substitutions affect proteins are keys to our basic understanding of protein function and evolution. Amino acid changes may affect protein function in a number of ways including direct perturbations of activity or indirect effects on protein folding and stability. We have analyzed 6,749 experimentally determined variant effects from multiplexed assays on abundance and activity in two proteins (NUDT15 and PTEN) to quantify these effects and find that a third of the variants cause loss of function, and about half of loss-of-function variants also have low cellular abundance. We analyze the structural and mechanistic origins of loss of function and use the experimental data to find residues important for enzymatic activity. We performed computational analyses of protein stability and evolutionary conservation and show how we may predict positions where variants cause loss of activity or abundance. In this way, our results link thermodynamic stability and evolutionary conservation to experimental studies of different properties of protein fitness landscapes.

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Kagami, Luciano Porto, Gabriele Orlando, Daniele Raimondi, Francois Ancien, Bhawna Dixit, Jose Gavaldá-García, Pathmanaban Ramasamy, Joel Roca-Martínez, Konstantina Tzavella, and Wim Vranken. "b2bTools: online predictions for protein biophysical features and their conservation." Nucleic Acids Research 49, W1 (May 31, 2021): W52—W59. http://dx.doi.org/10.1093/nar/gkab425.

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Abstract We provide integrated protein sequence-based predictions via https://bio2byte.be/b2btools/. The aim of our predictions is to identify the biophysical behaviour or features of proteins that are not readily captured by structural biology and/or molecular dynamics approaches. Upload of a FASTA file or text input of a sequence provides integrated predictions from DynaMine backbone and side-chain dynamics, conformational propensities, and derived EFoldMine early folding, DisoMine disorder, and Agmata β-sheet aggregation. These predictions, several of which were previously not available online, capture ‘emergent’ properties of proteins, i.e. the inherent biophysical propensities encoded in their sequence, rather than context-dependent behaviour (e.g. final folded state). In addition, upload of a multiple sequence alignment (MSA) in a variety of formats enables exploration of the biophysical variation observed in homologous proteins. The associated plots indicate the biophysical limits of functionally relevant protein behaviour, with unusual residues flagged by a Gaussian mixture model analysis. The prediction results are available as JSON or CSV files and directly accessible via an API. Online visualisation is available as interactive plots, with brief explanations and tutorial pages included. The server and API employ an email-free token-based system that can be used to anonymously access previously generated results.

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Malleshappa Gowder, Shambhu, Jhinuk Chatterjee, Tanusree Chaudhuri, and Kusum Paul. "Prediction and Analysis of Surface Hydrophobic Residues in Tertiary Structure of Proteins." Scientific World Journal 2014 (2014): 1–7. http://dx.doi.org/10.1155/2014/971258.

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The analysis of protein structures provides plenty of information about the factors governing the folding and stability of proteins, the preferred amino acids in the protein environment, the location of the residues in the interior/surface of a protein and so forth. In general, hydrophobic residues such as Val, Leu, Ile, Phe, and Met tend to be buried in the interior and polar side chains exposed to solvent. The present work depends on sequence as well as structural information of the protein and aims to understand nature of hydrophobic residues on the protein surfaces. It is based on the nonredundant data set of 218 monomeric proteins. Solvent accessibility of each protein was determined using NACCESS software and then obtained the homologous sequences to understand how well solvent exposed and buried hydrophobic residues are evolutionarily conserved and assigned the confidence scores to hydrophobic residues to be buried or solvent exposed based on the information obtained from conservation score and knowledge of flanking regions of hydrophobic residues. In the absence of a three-dimensional structure, the ability to predict surface accessibility of hydrophobic residues directly from the sequence is of great help in choosing the sites of chemical modification or specific mutations and in the studies of protein stability and molecular interactions.

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Elías-Villalobos, Alberto, Philippe Fort, and Dominique Helmlinger. "New insights into the evolutionary conservation of the sole PIKK pseudokinase Tra1/TRRAP." Biochemical Society Transactions 47, no. 6 (November 26, 2019): 1597–608. http://dx.doi.org/10.1042/bst20180496.

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Phosphorylation by protein kinases is a fundamental mechanism of signal transduction. Many kinase families contain one or several members that, although evolutionarily conserved, lack the residues required for catalytic activity. Studies combining structural, biochemical, and functional approaches revealed that these pseudokinases have crucial roles in vivo and may even represent attractive targets for pharmacological intervention. Pseudokinases mediate signal transduction by a diversity of mechanisms, including allosteric regulation of their active counterparts, assembly of signaling hubs, or modulation of protein localization. One such pseudokinase, named Tra1 in yeast and transformation/transcription domain-associated protein (TRRAP) in mammals, is the only member lacking all catalytic residues within the phosphatidylinositol 3-kinase related kinase (PIKK) family of kinases. PIKKs are related to the PI3K family of lipid kinases, but function as Serine/Threonine protein kinases and have pivotal roles in diverse processes such as DNA damage sensing and repair, metabolic control of cell growth, nonsense-mediated decay, or transcription initiation. Tra1/TRRAP is the largest subunit of two distinct transcriptional co-activator complexes, SAGA and NuA4/TIP60, which it recruits to promoters upon transcription factor binding. Here, we review our current knowledge on the Tra1/TRRAP pseudokinase, focusing on its role as a scaffold for SAGA and NuA4/TIP60 complex assembly and recruitment to chromatin. We further discuss its evolutionary history within the PIKK family and highlight recent findings that reveal the importance of molecular chaperones in pseudokinase folding, function, and conservation.

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Smelter, Dan F., Willem J. de Lange, Wenxuan Cai, Ying Ge, and J. Carter Ralphe. "The HCM-linked W792R mutation in cardiac myosin-binding protein C reduces C6 FnIII domain stability." American Journal of Physiology-Heart and Circulatory Physiology 314, no. 6 (June 1, 2018): H1179—H1191. http://dx.doi.org/10.1152/ajpheart.00686.2017.

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Cardiac myosin-binding protein C (cMyBP-C) is a functional sarcomeric protein that regulates contractility in response to contractile demand, and many mutations in cMyBP-C lead to hypertrophic cardiomyopathy (HCM). To gain insight into the effects of disease-causing cMyBP-C missense mutations on contractile function, we expressed the pathogenic W792R mutation (substitution of a highly conserved tryptophan residue by an arginine residue at position 792) in mouse cardiomyocytes lacking endogenous cMyBP-C and studied the functional effects using three-dimensional engineered cardiac tissue constructs (mECTs). Based on complete conservation of tryptophan at this location in fibronectin type II (FnIII) domains, we hypothesized that the W792R mutation affects folding of the C6 FnIII domain, destabilizing the mutant protein. Adenoviral transduction of wild-type (WT) and W792R cDNA achieved equivalent mRNA transcript abundance, but not equivalent protein levels, with W792R compared with WT controls. mECTs expressing W792R demonstrated abnormal contractile kinetics compared with WT mECTs that were nearly identical to cMyBP-C-deficient mECTs. We studied whether common pathways of protein degradation were responsible for the rapid degradation of W792R cMyBP-C. Inhibition of both ubiquitin-proteasome and lysosomal degradation pathways failed to increase full-length mutant protein abundance to WT equivalence, suggesting rapid cytosolic degradation. Bacterial expression of WT and W792R protein fragments demonstrated decreased mutant stability with altered thermal denaturation and increased susceptibility to trypsin digestion. These data suggest that the W792R mutation destabilizes the C6 FnIII domain of cMyBP-C, resulting in decreased full-length protein expression. This study highlights the vulnerability of FnIII-like domains to mutations that alter domain stability and further indicates that missense mutations in cMyBP-C can cause disease through a mechanism of haploinsufficiency. NEW & NOTEWORTHY This study is one of the first to describe a disease mechanism for a missense mutation in cardiac myosin-binding protein C linked to hypertrophic cardiomyopathy. The mutation decreases stability of the fibronectin type III domain and results in substantially reduced mutant protein expression dissonant to transcript abundance.

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Huang, Q., S. Liu, Y. Tang, S. Jin, and Y. Wang. "Studies on crystal structures, active-centre geometry and depurinating mechanism of two ribosome-inactivating proteins." Biochemical Journal 309, no. 1 (July 1, 1995): 285–98. http://dx.doi.org/10.1042/bj3090285.

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Two ribosome-inactivating proteins, trichosanthin and alpha-momorcharin, have been studied in the forms of complexes with ATP or formycin, by an X-ray-crystallographic method at 1.6-2.0 A (0.16-0.20 nm) resolution. The native alpha-momorcharin had been studied at 2.2 A resolution. Structures of trichosanthin were determined by a multiple isomorphous replacement method. Structures of alpha-momorcharin were determined by a molecular replacement method using refined trichosanthin as the searching model. Small ligands in all these complexes have been recognized and built on the difference in electron density. All these structures have been refined to achieve good results, both in terms of crystallography and of ideal geometry. These two proteins show considerable similarity in their three-dimensional folding and to that of related proteins. On the basis of these structures, detailed geometries of the active centres of these two proteins are described and are compared with those of related proteins. In all complexes the interactions between ligand atoms and protein atoms, including hydrophobic forces, aromatic stacking interactions and hydrogen bonds, are found to be specific towards the adenine base. The relationship between the sequence conservation of ribosome-inactivating proteins and their active-centre geometry was analysed. A depurinating mechanism of ribosome-inactivating proteins is proposed on the basis of these results. The N-7 atom of the substrate base group is proposed to be protonated by an acidic residue in the active centre.

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Dzichenka, Yaraslau V., Eugene S. Gudny, and Sergei A. Usanov. "STRUCTURAL FEATURES OF HUMAN CYTOCHROME P450 7B1 WITH AN AMINO ACID SUBSTITUTION OF Phe470Ile." Doklady of the National Academy of Sciences of Belarus 62, no. 4 (September 13, 2018): 423–31. http://dx.doi.org/10.29235/1561-8323-2018-62-4-423-431.

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To study the influence of the amino acid substitution of Phe470Ile, correlating with the spastic paraplegia of type 5, on the structure of human cytochrome P450 7B1, the spatial full-atomic models of this enzyme and its mutant form were created. It was found that Phe470 does not influence directly the catalytic properties of the enzyme because of its localization far from the active site. It was shown that the residue under investigation belongs to a highly conservative region of the protein structure and can influence the CYP7B1 correct folding. In particular, the amino acid substitution of Phe470Ile increases rigidity and stability of sterol 7α-hydroxylase. This can be a reason of changes in the CYP7B1 hydroxylase activity in relation to neurosteroids.

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Rickert, Mathias, Jochen Seissler, Werner Dangel, Helga Lorenz, and Wiltrud Richter. "Fusion Proteins for Combined Analysis of Autoantibodies to the 65-kDa Isoform of Glutamic Acid Decarboxylase and Islet Antigen-2 in Insulin-dependent Diabetes Mellitus." Clinical Chemistry 47, no. 5 (May 1, 2001): 926–34. http://dx.doi.org/10.1093/clinchem/47.5.926.

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Abstract Background: Prediction, risk assessment, and diagnosis of autoimmune diseases often rely on detection of autoantibodies directed to multiple target antigens, such as the 65-kDa isoform of glutamic acid decarboxylase (GAD65-abs) and the tyrosine phosphatase-like protein islet antigen-2 (IA2-abs), the two major subspecificities of islet cell antibodies (ICAs) associated with insulin-dependent diabetes mellitus. We hypothesized that a combination of autoantigens in a fusion protein unifying the important immunodominant epitopes could provide an efficient target for cost-effective, one-step screening of sera. Methods: Chimeric proteins composed of GAD65 and IA2 residues were constructed, analyzed for their immune reactivity with monoclonal antibodies and sera, and used in a diagnostic assay with 35S-labeled protein as antigen. Results: Length and order of GAD65 and IA2 sequences were critical for conservation of the conformational epitopes in the fusion protein. Among four chimera tested, only IA2(606–979)/GAD65(1–585) retained wild-type-like folding of GAD65 and IA2 domains and yielded a stable protein after baculovirus expression. Reactivity of GAD65 antibody- and IA2 antibody-positive sera from patients newly diagnosed with insulin-dependent diabetes mellitus, from ICA-positive prediabetics, and from ICA-positive first-degree relatives demonstrated conservation of the relevant autoreactive epitopes. The assay based on the in vitro translated fusion antigen had a sensitivity and specificity identical to those for detection of GAD65- and IA2-abs based on the two separate GAD65 and IA2 proteins. Conclusions: Autoantigens such as GAD65 and IA2 can be combined successfully in a fusion protein of similar immune reactivity. This allows simultaneous detection of GAD65- and IA2-abs in a one-step screening assay and cost-effective identification of positive individuals at risk of diabetes or at onset of disease.

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Andreou, Athena, Petros Giastas, Elias Christoforides, and Elias Eliopoulos. "Structural and Evolutionary Insights within the Polysaccharide Deacetylase Gene Family of Bacillus anthracis and Bacillus cereus." Genes 9, no. 8 (July 31, 2018): 386. http://dx.doi.org/10.3390/genes9080386.

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Functional and folding constraints impose interdependence between interacting sites along the protein chain that are envisaged through protein sequence evolution. Studying the influence of structure in phylogenetic models requires detailed and reliable structural models. Polysaccharide deacetylases (PDAs), members of the carbohydrate esterase family 4, perform mainly metal-dependent deacetylation of O- or N-acetylated polysaccharides such as peptidoglycan, chitin and acetylxylan through a conserved catalytic core termed the NodB homology domain. Genomes of Bacillus anthracis and its relative Bacillus cereus contain multiple genes of putative or known PDAs. A comparison of the functional domains of the recently determined PDAs from B. anthracis and B. cereus and multiple amino acid and nucleotide sequence alignments and phylogenetic analysis performed on these closely related species showed that there were distinct differences in binding site formation, despite the high conservation on the protein sequence, the folding level and the active site assembly. This may indicate that, subject to biochemical verification, the binding site-forming sequence fragments are under functionally driven evolutionary pressure to accommodate and recognize distinct polysaccharide residues according to cell location, use, or environment. Finally, we discuss the suggestion of the paralogous nature of at least two genes of B. anthracis, ba0330 and ba0331, via specific differences in gene sequence, protein structure, selection pressure and available localization patterns. This study may contribute to understanding the mechanisms under which sequences evolve in their structures and how evolutionary processes enable structural variations.

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Caoili, Salvador Eugenio C. "Expressing Redundancy among Linear-Epitope Sequence Data Based on Residue-Level Physicochemical Similarity in the Context of Antigenic Cross-Reaction." Advances in Bioinformatics 2016 (May 4, 2016): 1–13. http://dx.doi.org/10.1155/2016/1276594.

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Epitope-based design of vaccines, immunotherapeutics, and immunodiagnostics is complicated by structural changes that radically alter immunological outcomes. This is obscured by expressing redundancy among linear-epitope data as fractional sequence-alignment identity, which fails to account for potentially drastic loss of binding affinity due to single-residue substitutions even where these might be considered conservative in the context of classical sequence analysis. From the perspective of immune function based on molecular recognition of epitopes, functional redundancy of epitope data (FRED) thus may be defined in a biologically more meaningful way based on residue-level physicochemical similarity in the context of antigenic cross-reaction, with functional similarity between epitopes expressed as the Shannon information entropy for differential epitope binding. Such similarity may be estimated in terms of structural differences between an immunogen epitope and an antigen epitope with reference to an idealized binding site of high complementarity to the immunogen epitope, by analogy between protein folding and ligand-receptor binding; but this underestimates potential for cross-reactivity, suggesting that epitope-binding site complementarity is typically suboptimal as regards immunologic specificity. The apparently suboptimal complementarity may reflect a tradeoff to attain optimal immune function that favors generation of immune-system components each having potential for cross-reactivity with a variety of epitopes.

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Theune, Marius L., Sabine Hummel, Nina Jaspert, Marcel Lafos, Dierk Wanke, and Dierk Wanke. "Dimerization of the BASIC PENTACYSTEINE Domain in Plant GAGA-Factors is Mediated by Disulfide Bonds and Required for DNA-Binding." Journal of Advances in Plant Biology 1, no. 1 (August 19, 2017): 26–39. http://dx.doi.org/10.14302/issn.2638-4469.japb-17-1563.

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GAGA-binding proteins in plants are encoded by the BARLEY B-RECOMBINANT / BASIC PENTACYSTEINE (BBR/BPC) family, which can be spilt into several groups on the basis of sequence divergence. The proteins of the different groups share an evolutionary conserved BASIC PENTACYSTEINE (BPC) domain at their very C-terminus that is important for DNA binding. Hallmark of this domain are five Cysteines at defined positions and spacing, which are considered to form a zinc-finger like structure that is involved in GAGA-motif recognition. Here, we report the formation of stabile homodimers between Arabidopsis thaliana group I member BPC1 or between group II member BPC6 in SDS-PAGE. Serial mutations of the highly conserved five Cysteines in the BPC domain of Arabidopsis thaliana BPC1 were tested for their capacity to bind to GAGA-motifs by DPI-ELISA. Our results do not support the idea of a direct involvement of these residues in making physical contact with the DNA, e.g. by formation of a zinc-finger structure. Instead, the data implies an indispensable function for the five Cysteines in homodimerization and stabilization of the protein structure by disulfide bonds. Accordingly, protein folding and structure prediction suggests the formation of a scaffold for dimerization that is supported by three intermolecular and one intramolecular S-S bond. The high degree of conservation between the BPC domains from the different groups and from different species denotes that this role for the five Cysteines might be evolutionary retained.

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Chilukoti, Neeraja, C. M. Santosh Kumar, and Shekhar C. Mande. "GroEL2 of Mycobacterium tuberculosis Reveals the Importance of Structural Pliability in Chaperonin Function." Journal of Bacteriology 198, no. 3 (November 9, 2015): 486–97. http://dx.doi.org/10.1128/jb.00844-15.

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ABSTRACTIntracellular protein folding is mediated by molecular chaperones, the best studied among which are the chaperonins GroEL and GroES. Conformational changes and allosteric transitions between different metastable states are hallmarks of the chaperonin mechanism. These conformational transitions between three structural domains of GroEL are anchored at two hinges. Although hinges are known to be critical for mediating the communication between different domains of GroEL, the relative importance of hinges on GroEL oligomeric assembly, ATPase activity, conformational changes, and functional activity is not fully characterized. We have exploited the inability ofMycobacterium tuberculosisGroEL2 to functionally complement anEscherichia coligroELmutant to address the importance of hinge residues in the GroEL mechanism. Various chimeras ofM. tuberculosisGroEL2 andE. coliGroEL allowed us to understand the role of hinges and dissect the consequences of oligomerization and substrate binding capability on conformational transitions. The present study explains the concomitant conformational changes observed with GroEL hinge variants and is best supported by the normal mode analysis.IMPORTANCEConformational changes and allosteric transitions are hallmarks of the chaperonin mechanism. We have exploited the inability ofM. tuberculosisGroEL2 to functionally complement a strain ofE. coliin whichgroELexpression is repressed to address the importance of hinges. The significance of conservation at the hinge regions stands out as a prominent feature of the GroEL mechanism in binding to GroES and substrate polypeptides. The hinge residues play a significant role in the chaperonin activityin vivoandin vitro.

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Angira, Deekshi, Nalini Natarajan, Samir R. Dedania, Darshan H. Patel, and Vijay Thiruvenkatam. "Characterization of P. aeruginosa Glucose 6- Phosphate Isomerase: A Functional Insight via In-Vitro Activity Study." Current Topics in Medicinal Chemistry 20, no. 29 (November 20, 2020): 2651–61. http://dx.doi.org/10.2174/1568026620666200820153751.

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Background: Glucose-6-phosphate isomerase (G6PI) catalyses the second step in glycolysis in the reversible interconversion of an aldohexose glucose 6-phosphate, a six membered ring moiety to a ketohexose, fructose 6-phosphate five membered ring moiety. This enzyme is of utmost importance due to its multifunctional role like neuroleukin, autocrine motility factor, etc. in various species. G6PI from Pseudomonas aeruginosa is less explored for its moonlighting properties. These properties can be predicted by studying the active site conservation of residues and their interaction with the specific ligand. Methods: Here, we study the G6PI in a self-inducible construct in bacterial expression system with its purification using Ni-NTA chromatography. The secondary structure of pure G6PI is estimated using circular dichroism to further predict the proper folding form of the protein. The bioactivity of the purified enzyme is quantified using phosphoglucose isomerase colorimetric kit with a value of 12.5 mU/mL. Differential scanning fluorimetry and isothermal titration calorimetry were employed to monitor the interaction of G6PI with its competitive inhibitor, erythrose 4-phosphate and calculated the Tm, Kd and IC50 values. Further, the homology model for the protein was prepared to study the interaction with the erythrose 4-phosphate. MD simulation of the complex was performed at 100 ns to identify the binding interactions. Results: We identified hydrogen bonds and water bridges dominating the interactions in the active site holding the protein and ligand with strong affinity. Conclusion : G6PI was successfully crystallized and data has been collected at 6Å. We are focused on improving the crystal quality for obtaining higher resolution data.

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Yao, Xin-Qiu, and Zhen-Su She. "Key residue-dominated protein folding dynamics." Biochemical and Biophysical Research Communications 373, no. 1 (August 2008): 64–68. http://dx.doi.org/10.1016/j.bbrc.2008.05.179.

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McIntyre, C. L., J. Drenth, N. Gonzalez, R. G. Henzell, and D. R. Jordan. "Molecular characterization of the waxy locus in sorghum." Genome 51, no. 7 (July 2008): 524–33. http://dx.doi.org/10.1139/g08-035.

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A comparison of approximately 4.5 kb of nucleotide sequence from the waxy locus (the granule-bound starch synthase I [GBSS I] locus) from a waxy line, BTxARG1, and a non-waxy line, QL39, revealed an extremely high level of sequence conservation. Among a total of 24 nucleotide differences and 9 indels, only 2 nucleotide changes resulted in altered amino acid residues. Protein folding prediction software suggested that one of the amino acid changes (Glu to His) may result in an altered protein structure, which may explain the apparently inactive GBSS I present in BTxARG1. This SNP was not found in the second waxy line, RTx2907, which does not produce GBSS I, and no other SNPs or indels were found in the approximately 4 kb of sequence obtained from RTx2907. Using one indel, the waxy locus was mapped to sorghum chromosome SBI-10, which is syntenous to maize chromosome 9; the waxy locus has been mapped to this maize chromosome. The distribution of indels in a diverse set of sorghum germplasm suggested that there are two broad types of non-waxy GBSS I alleles, each type comprising several alleles, and that the two waxy alleles in BTxARG1 and RTx2907 have evolved from one of the non-waxy allele types. The Glu/His polymorphism was found only in BTxARG1 and derived lines and has potential as a perfect marker for the BTxARG1 source of the waxy allele at the GBSS I locus. The indels correctly predicted the non-waxy phenotype in approximately 65% of diverse sorghum germplasm. The indels co-segregated perfectly with phenotype in two sorghum populations derived from crosses between a waxy and a non-waxy sorghum line, correctly identifying heterozygous lines. Thus, these indel markers or sequence-based SNP markers can be used to follow waxy alleles in sorghum breeding programs in selected pedigrees.

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Pattabiraman, Nagarajan. "Role of residue packing in protein folding." TrAC Trends in Analytical Chemistry 22, no. 8 (September 2003): 554–60. http://dx.doi.org/10.1016/s0165-9936(03)00906-3.

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Plaxco, Kevin W., Stefan Larson, Ingo Ruczinski, David S. Riddle, Edward C. Thayer, Brian Buchwitz, Alan R. Davidson, and David Baker. "Evolutionary conservation in protein folding kinetics." Journal of Molecular Biology 298, no. 2 (April 2000): 303–12. http://dx.doi.org/10.1006/jmbi.1999.3663.

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Gromiha, M. Michael, and S. Selvaraj. "Inter-residue interactions in protein folding and stability." Progress in Biophysics and Molecular Biology 86, no. 2 (October 2004): 235–77. http://dx.doi.org/10.1016/j.pbiomolbio.2003.09.003.

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NARAYANA, S. V. L., and PATRICK ARGOS. "Residue contacts in protein structures and implications for protein folding." International Journal of Peptide and Protein Research 24, no. 1 (January 12, 2009): 25–39. http://dx.doi.org/10.1111/j.1399-3011.1984.tb00924.x.

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Yan, Zhiqiang, and Jin Wang. "Funneled energy landscape unifies principles of protein binding and evolution." Proceedings of the National Academy of Sciences 117, no. 44 (October 16, 2020): 27218–23. http://dx.doi.org/10.1073/pnas.2013822117.

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Most proteins have evolved to spontaneously fold into native structure and specifically bind with their partners for the purpose of fulfilling biological functions. According to Darwin, protein sequences evolve through random mutations, and only the fittest survives. The understanding of how the evolutionary selection sculpts the interaction patterns for both biomolecular folding and binding is still challenging. In this study, we incorporated the constraint of functional binding into the selection fitness based on the principle of minimal frustration for the underlying biomolecular interactions. Thermodynamic stability and kinetic accessibility were derived and quantified from a global funneled energy landscape that satisfies the requirements of both the folding into the stable structure and binding with the specific partner. The evolution proceeds via a bowl-like evolution energy landscape in the sequence space with a closed-ring attractor at the bottom. The sequence space is increasingly reduced until this ring attractor is reached. The molecular-interaction patterns responsible for folding and binding are identified from the evolved sequences, respectively. The residual positions participating in the interactions responsible for folding are highly conserved and maintain the hydrophobic core under additional evolutionary constraints of functional binding. The positions responsible for binding constitute a distributed network via coupling conservations that determine the specificity of binding with the partner. This work unifies the principles of protein binding and evolution under minimal frustration and sheds light on the evolutionary design of proteins for functions.

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Karlin, Samuel, Michael Zuker, and Luciano Brocchieri. "Measuring Residue Association in Protein Structures Possible Implications for Protein Folding." Journal of Molecular Biology 239, no. 2 (June 1994): 227–48. http://dx.doi.org/10.1006/jmbi.1994.1365.

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Balbach, J., V. Forge, W. S. Lau, J. A. Jones, N. A. J. van Nuland, and C. M. Dobson. "Detection of residue contacts in a protein folding intermediate." Proceedings of the National Academy of Sciences 94, no. 14 (July 8, 1997): 7182–85. http://dx.doi.org/10.1073/pnas.94.14.7182.

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Gromiha, Michael, and Samuel Selvaraj. "Inter-residue Interactions in Protein Structures : Applications to Protein Folding and Stability." Seibutsu Butsuri 43, supplement (2003): S57. http://dx.doi.org/10.2142/biophys.43.s57_1.

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Huang, Shanran, and Jitao T. Huang. "Inter-residue interaction is a determinant of protein folding kinetics." Journal of Theoretical Biology 317 (January 2013): 224–28. http://dx.doi.org/10.1016/j.jtbi.2012.10.003.

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Arnold, Ulrich, Matthew P. Hinderaker, Jens Köditz, Ralph Golbik, Renate Ulbrich-Hofmann, and Ronald T. Raines. "Protein Prosthesis: A Nonnatural Residue Accelerates Folding and Increases Stability." Journal of the American Chemical Society 125, no. 25 (June 2003): 7500–7501. http://dx.doi.org/10.1021/ja0351239.

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Ng, A. S. Angie, and R. Manjunatha Kini. "Structural Determinants in Protein Folding: A Single Conserved Hydrophobic Residue Determines Folding of EGF Domains." ACS Chemical Biology 8, no. 1 (October 24, 2012): 161–69. http://dx.doi.org/10.1021/cb300445a.

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Nikiforovich, Gregory V., Niels H. Andersen, R. Matthew Fesinmeyer, and Carl Frieden. "Possible locally driven folding pathways of TC5b, a 20-residue protein." Proteins: Structure, Function, and Genetics 52, no. 2 (June 23, 2003): 292–302. http://dx.doi.org/10.1002/prot.10409.

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Song, Xiangfei, Tianhang Lv, Jingfei Chen, Jia Wang, and Lishan Yao. "Characterization of Residue Specific Protein Folding and Unfolding Dynamics in Cells." Journal of the American Chemical Society 141, no. 29 (July 15, 2019): 11363–66. http://dx.doi.org/10.1021/jacs.9b04435.

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Bueno, Carlos A., Davit A. Potoyan, Ryan R. Cheng, and Peter G. Wolynes. "Prediction of Changes in Protein Folding Stability Upon Single Residue Mutations." Biophysical Journal 114, no. 3 (February 2018): 199a. http://dx.doi.org/10.1016/j.bpj.2017.11.1114.

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Satoh, Daisuke, Kentaro Shimizu, Shugo Nakamura, and Tohru Terada. "Folding free-energy landscape of a 10-residue mini-protein, chignolin." FEBS Letters 580, no. 14 (May 11, 2006): 3422–26. http://dx.doi.org/10.1016/j.febslet.2006.05.015.

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Mary, Rajathei David, Mani K. Saravanan, and Samuel Selvaraj. "Conservation of inter-residue interactions and prediction of folding rates of domain repeats." Journal of Biomolecular Structure and Dynamics 33, no. 3 (April 7, 2014): 534–51. http://dx.doi.org/10.1080/07391102.2014.894944.

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Wang, Bing, Hau San Wong, and De-Shuang Huang. "Inferring Protein-Protein Interacting Sites Using Residue Conservation and Evolutionary Information." Protein & Peptide Letters 13, no. 10 (October 1, 2006): 999–1005. http://dx.doi.org/10.2174/092986606778777498.

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Li, Jing-Jing, De-Shuang Huang, Bing Wang, and Pen Chen. "Identifying protein–protein interfacial residues in heterocomplexes using residue conservation scores." International Journal of Biological Macromolecules 38, no. 3-5 (May 2006): 241–47. http://dx.doi.org/10.1016/j.ijbiomac.2006.02.024.

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Giri Rao, V. V. Hemanth, and Shachi Gosavi. "On the folding of a structurally complex protein to its metastable active state." Proceedings of the National Academy of Sciences 115, no. 9 (January 17, 2018): 1998–2003. http://dx.doi.org/10.1073/pnas.1708173115.

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For successful protease inhibition, the reactive center loop (RCL) of the two-domain serine protease inhibitor, α1-antitrypsin (α1-AT), needs to remain exposed in a metastable active conformation. The α1-AT RCL is sequestered in a β-sheet in the stable latent conformation. Thus, to be functional, α1-AT must always fold to a metastable conformation while avoiding folding to a stable conformation. We explore the structural basis of this choice using folding simulations of coarse-grained structure-based models of the two α1-AT conformations. Our simulations capture the key features of folding experiments performed on both conformations. The simulations also show that the free energy barrier to fold to the latent conformation is much larger than the barrier to fold to the active conformation. An entropically stabilized on-pathway intermediate lowers the barrier for folding to the active conformation. In this intermediate, the RCL is in an exposed configuration, and only one of the two α1-AT domains is folded. In contrast, early conversion of the RCL into a β-strand increases the coupling between the two α1-AT domains in the transition state and creates a larger barrier for folding to the latent conformation. Thus, unlike what happens in several proteins, where separate regions promote folding and function, the structure of the RCL, formed early during folding, determines both the conformational and the functional fate of α1-AT. Further, the short 12-residue RCL modulates the free energy barrier and the folding cooperativity of the large 370-residue α1-AT. Finally, we suggest experiments to test the predicted folding mechanism for the latent state.

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DUAN, YUHUA, BOOJALA V. B. REDDY, and YIANNIS N. KAZNESSIS. "RESIDUE CONSERVATION INFORMATION FOR GENERATING NEAR-NATIVE STRUCTURES IN PROTEIN–PROTEIN DOCKING." Journal of Bioinformatics and Computational Biology 04, no. 04 (August 2006): 793–806. http://dx.doi.org/10.1142/s0219720006002223.

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Motivation: Protein–protein docking algorithms typically generate large numbers of possible complex structures with only a few of them resembling the native structure. Recently (Duan et al., Protein Sci, 14:316–218, 2005), it was observed that the surface density of conserved residue positions is high at the interface regions of interacting protein surfaces, except for antibody–antigen complexes, where a lesser number of conserved positions than average is observed at the interface regions. Using this observation, we identified putative interacting regions on the surface of interacting partners and significantly improved docking results by assigning top ranks to near-native complex structures. In this paper, we combine the residue conservation information with a widely used shape complementarity algorithm to generate candidate complex structures with a higher percentage of near-native structures (hits). What is new in this work is that the conservation information is used early in the generation stage and not only in the ranking stage of the docking algorithm. This results in a significantly larger number of generated hits and an improved predictive ability in identifying the native structure of protein–protein complexes. Results: We report on results from 48 well-characterized protein complexes, which have enough residue conservation information from the same 59 benchmark complexes used in our previous work. We compute conservation indices of residue positions on the surfaces of interacting proteins using available homologous sequences from UNIPROT and calculate the solvent accessible surface area. We combine this information with shape-complementarity scores to generate candidate protein–protein complex structures. When compared with pure shape-complementarity algorithms, performed by FTDock, our method results in significantly more hits, with the improvement being over 100% in many instances. We demonstrate that residue conservation information is useful not only in refinement and scoring of docking solutions, but also helpful in enrichment of near-native-structures during the generation of candidate geometries of complex structures.

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WANG, LU-YONG. "COVARIATION ANALYSIS OF LOCAL AMINO ACID SEQUENCES IN RECURRENT PROTEIN LOCAL STRUCTURES." Journal of Bioinformatics and Computational Biology 03, no. 06 (December 2005): 1391–409. http://dx.doi.org/10.1142/s0219720005001648.

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Local structural information is supposed to be frequently encoded in local amino acid sequences. Previous research only indicated that some local structure positions have specific residue preferences in some particular local structures. However, correlated pairwise replacements for interacting residues in recurrent local structural motifs from unrelated proteins have not been studied systematically. We introduced a new method fusing statistical covariation analysis and local structure-based alignment. Systematic analysis of structure-based multiple alignments of recurrent local structures from unrelated proteins in representative subset of Protein Databank indicates that covarying residue pairs with statistical significance exist in local structural motifs, in particular β-turns and helix caps. These residue pairs are mostly linked through polar functional groups with direct or indirect hydrogen bonding. Hydrophobic interaction is also a major factor in constraining pairwise amino acid residue replacement in recurrent local structures. We also found correlated residue pairs that are not clearly linked with through-space interactions. The physical constrains underlying these covariations are less clear. Overall, covarying residue pairs with statistical significance exist in local structures from unrelated proteins. The existence of sequence covariations in local structural motifs from unrelated proteins indicates that many relics of local relations are still retained in the tertiary structures after protein folding. It supports the notion that some local structural information is encoded in local sequences and the local structural codes could play important roles in determining native state protein folding topology.

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Scheraga, Harold A. "My 65 years in protein chemistry." Quarterly Reviews of Biophysics 48, no. 2 (April 8, 2015): 117–77. http://dx.doi.org/10.1017/s0033583514000134.

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AbstractThis is a tour of a physical chemist through 65 years of protein chemistry from the time when emphasis was placed on the determination of the size and shape of the protein molecule as a colloidal particle, with an early breakthrough by James Sumner, followed by Linus Pauling and Fred Sanger, that a protein was a real molecule, albeit a macromolecule. It deals with the recognition of the nature and importance of hydrogen bonds and hydrophobic interactions in determining the structure, properties, and biological function of proteins until the present acquisition of an understanding of the structure, thermodynamics, and folding pathways from a linear array of amino acids to a biological entity. Along the way, with a combination of experiment and theoretical interpretation, a mechanism was elucidated for the thrombin-induced conversion of fibrinogen to a fibrin blood clot and for the oxidative-folding pathways of ribonuclease A. Before the atomic structure of a protein molecule was determined by x-ray diffraction or nuclear magnetic resonance spectroscopy, experimental studies of the fundamental interactions underlying protein structure led to several distance constraints which motivated the theoretical approach to determine protein structure, and culminated in the Empirical Conformational Energy Program for Peptides (ECEPP), an all-atom force field, with which the structures of fibrous collagen-like proteins and the 46-residue globular staphylococcal protein A were determined. To undertake the study of larger globular proteins, a physics-based coarse-grained UNited-RESidue (UNRES) force field was developed, and applied to the protein-folding problem in terms of structure, thermodynamics, dynamics, and folding pathways. Initially, single-chain and, ultimately, multiple-chain proteins were examined, and the methodology was extended to protein–protein interactions and to nucleic acids and to protein–nucleic acid interactions. The ultimate results led to an understanding of a variety of biological processes underlying natural and disease phenomena.

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Jeong, Min-Joong. "Computational Three-Residue Fragment Assembly and Folding Optimization for Protein Structure Design." Journal of the Korean Physical Society 55, no. 5(2) (November 14, 2009): 2235–41. http://dx.doi.org/10.3938/jkps.55.2235.

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Nagy, Joanna K., and Charles R. Sanders. "A Critical Residue in the Folding Pathway of an Integral Membrane Protein†." Biochemistry 41, no. 29 (July 2002): 9021–25. http://dx.doi.org/10.1021/bi020318z.

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Huang, He, and Xinqi Gong. "A Review of Protein Inter-residue Distance Prediction." Current Bioinformatics 15, no. 8 (January 1, 2021): 821–30. http://dx.doi.org/10.2174/1574893615999200425230056.

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Proteins are large molecules consisting of a linear sequence of amino acids. Protein performs biological functions with specific 3D structures. The main factors that drive proteins to form these structures are constraint between residues. These constraints usually lead to important inter-residue relationships, including short-range inter-residue contacts and long-range interresidue distances. Thus, a highly accurate prediction of inter-residue contact and distance information is of great significance for protein tertiary structure computations. Some methods have been proposed for inter-residue contact prediction, most of which focus on contact map prediction and some reviews have summarized the progresses. However, inter-residue distance prediction is found to provide better guidance for protein structure prediction than contact map prediction in recent years. The methods for inter-residue distance prediction can be roughly divided into two types according to the consideration of distance value: one is based on multi-classification with discrete value and the other is based on regression with continuous value. Here, we summarize these algorithms and show that they have obtained good results. Compared to contact map prediction, distance map prediction is in its infancy. There is a lot to do in the future including improving distance map prediction precision and incorporating them into residue-residue distanceguided ab initio protein folding.

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Wagaman, Amy S., and Sheila S. Jaswal. "Capturing protein folding-relevant topology via absolute contact order variants." Journal of Theoretical and Computational Chemistry 13, no. 01 (February 2014): 1450005. http://dx.doi.org/10.1142/s0219633614500059.

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Absolute contact order is one of the simplest parameters used to predict protein folding rates. Many variants of contact order (CO) have been applied to highlight different aspects of contact neighborhoods and their relationship to folding. However, a systematic study of the influence of CO variants on correlation with folding rate has not been performed for a large combined set of multi- and two-state proteins. We explore different contact neighborhoods and resulting CO by varying the distance thresholds and weighting of sequence separation for heavy atom and residue-based counting methods for a set of 136 proteins diverse across folding and structural classes. We examine the changes in contact neighborhoods and compare correlations with our CO variants and the protein folding rates across our data set as well as by folding type and structural class. Different CO variants lead to the strongest correlations within each protein structural class. Our results demonstrate that backbone topology at a distance beyond where energetic interactions dominate is able to capture folding determinants, and suggest that more sensitive methods of characterizing contact relationships may improve ln kf prediction for diverse protein sets.

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GAO, KAIFU, and MINGHUI YANG. "MOLECULAR DYNAMICS SIMULATIONS OF HELIX BUNDLE PROTEINS USING UNRES FORCE FIELD AND ALL-ATOM FORCE FIELD." Journal of Theoretical and Computational Chemistry 11, no. 06 (December 2012): 1201–15. http://dx.doi.org/10.1142/s0219633612500800.

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We have investigated the folding of two helix-bundle proteins, 36-residue Villin headpiece and 56-residue E-domain of Staphylococcal protein A, by combining molecular dynamics (MD) simulations with Coarse-Grained United-Residue (UNRES) Force Field and all-atom force field. Starting from extended structures, each of the proteins was folded to a stable structure within a short time frame using the UNRES model. However, the secondary structures of helices were not well formed. Further refinement using MD simulations with the all-atom force field was able to fold the protein structure into the native-like state with the smallest main-chain root-mean-square deviation of around 3 Å. Detailed analysis of the folding trajectories was presented and the performance of GPU-based MD simulations was also discussed.

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Papp, Dóra, Imola Csilla Szigyártó, Bengt Nordén, András Perczel, and Tamás Beke-Somfai. "Structural Water Stabilizes Protein Motifs in Liquid Protein Phase: The Folding Mechanism of Short β-Sheets Coupled to Phase Transition." International Journal of Molecular Sciences 22, no. 16 (August 10, 2021): 8595. http://dx.doi.org/10.3390/ijms22168595.

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Macromolecular associates, such as membraneless organelles or lipid-protein assemblies, provide a hydrophobic environment, i.e., a liquid protein phase (LP), where folding preferences can be drastically altered. LP as well as the associated phase change from water (W) is an intriguing phenomenon related to numerous biological processes and also possesses potential in nanotechnological applications. However, the energetic effects of a hydrophobic yet water-containing environment on protein folding are poorly understood. Here, we focus on small β-sheets, the key motifs of proteins, undergoing structural changes in liquid–liquid phase separation (LLPS) and also model the mechanism of energy-coupled unfolding, e.g., in proteases, during W → LP transition. Due to the importance of the accurate description for hydrogen bonding patterns, the employed models were studied by using quantum mechanical calculations. The results demonstrate that unfolding is energetically less favored in LP by ~0.3–0.5 kcal·mol−1 per residue in which the difference further increased by the presence of explicit structural water molecules, where the folded state was preferred by ~1.2–2.3 kcal·mol−1 per residue relative to that in W. Energetics at the LP/W interfaces was also addressed by theoretical isodesmic reactions. While the models predict folded state preference in LP, the unfolding from LP to W renders the process highly favorable since the unfolded end state has >1 kcal·mol−1 per residue excess stabilization.

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Journal articles on the topic 'Residue conservation; Protein folding'

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