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      Implication of the cause of differences in 3D structures of proteins with high sequence identity based on analyses of amino acid sequences and 3D structures

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          Abstract

          Background

          Proteins that share a high sequence homology while exhibiting drastically different 3D structures are investigated in this study. Recently, artificial proteins related to the sequences of the GA and IgG binding GB domains of human serum albumin have been designed. These artificial proteins, referred to as GA and GB, share 98% amino acid sequence identity but exhibit different 3D structures, namely, a 3α bundle versus a 4β + α structure. Discriminating between their 3D structures based on their amino acid sequences is a very difficult problem. In the present work, in addition to using bioinformatics techniques, an analysis based on inter-residue average distance statistics is used to address this problem.

          Results

          It was hard to distinguish which structure a given sequence would take only with the results of ordinary analyses like BLAST and conservation analyses. However, in addition to these analyses, with the analysis based on the inter-residue average distance statistics and our sequence tendency analysis, we could infer which part would play an important role in its structural formation.

          Conclusions

          The results suggest possible determinants of the different 3D structures for sequences with high sequence identity. The possibility of discriminating between the 3D structures based on the given sequences is also discussed.

          Electronic supplementary material

          The online version of this article (doi:10.1186/1756-0500-7-654) contains supplementary material, which is available to authorized users.

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          Most cited references 26

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          Topological and energetic factors: what determines the structural details of the transition state ensemble and "en-route" intermediates for protein folding? An investigation for small globular proteins.

          Recent experimental results suggest that the native fold, or topology, plays a primary role in determining the structure of the transition state ensemble, at least for small, fast-folding proteins. To investigate the extent of the topological control of the folding process, we studied the folding of simplified models of five small globular proteins constructed using a Go-like potential to retain the information about the native structures but drastically reduce the energetic frustration and energetic heterogeneity among residue-residue native interactions. By comparing the structure of the transition state ensemble (experimentally determined by Phi-values) and of the intermediates with those obtained using our models, we show that these energetically unfrustrated models can reproduce the global experimentally known features of the transition state ensembles and "en-route" intermediates, at least for the analyzed proteins. This result clearly indicates that, as long as the protein sequence is sufficiently minimally frustrated, topology plays a central role in determining the folding mechanism. Copyright 2000 Academic Press.
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            The origins of asymmetry in the folding transition states of protein L and protein G.

            Topology has been shown to be an important determinant of many features of protein folding; however, the delineation of sequence effects on folding remains obscure. Furthermore, differentiation between the two influences proves difficult due to their intimate relationship. To investigate the effect of sequence in the absence of significant topological differences, we examined the folding mechanisms of segment B1 peptostreptococcal protein L and segment B1 of streptococcal protein G. These proteins share the same highly symmetrical topology. Despite this symmetry, neither protein folds through a symmetrical transition state. We analyzed the origins of this difference using theoretical models. We found that the strength of the interactions present in the N-terminal hairpin of protein L causes this hairpin to form ahead of the C-terminal hairpin. The difference in chain entropy associated with the formation of the hairpins of protein G proves sufficient to beget initiation of folding at the shorter C-terminal hairpin. Our findings suggest that the mechanism of folding may be understood by examination of the free energy associated with the formation of partially folded microstates.
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              Roles of native topology and chain-length scaling in protein folding: a simulation study with a Go-like model.

               N Koga,  Shoji Takada (2001)
              We perform folding simulations on 18 small proteins with using a simple Go-like protein model and analyze the folding rate constants, characteristics of the transition state ensemble, and those of the denatured states in terms of native topology and chain length. Near the folding transition temperature, the folding rate k(F) scales as k(F) approximately exp(-c RCO N(0.6)) where RCO and N are the relative contact order and number of residues, respectively. Here the topology RCO dependence of the rates is close to that found experimentally (k(F) approximately exp(-c RCO)), while the chain length N dependence is in harmony with the predicted scaling property (k(F) approximately exp(-c N(2/3))). Thus, this may provides a unified scaling law in folding rates at the transition temperature, k(F) approximately exp(-c RCO N(2/3)). The degree of residual structure in the denatured state is highly correlated with RCO, namely, proteins with smaller RCO tend to have more ordered structure in the denatured state. This is consistent with the observation that many helical proteins such as myoglobin and protein A, have partial helices, in the denatured states. The characteristics of the transition state ensemble calculated by the current model, which uses native topology but not sequence specific information, are consistent with experimental phi-value data for about half of proteins. Copyright 2001 Academic Press.
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                Author and article information

                Contributors
                cb006060@ed.ritsumei.ac.jp
                m-sugita@fc.ritsumei.ac.jp
                tkikuchi@sk.ritsumei.ac.jp
                Journal
                BMC Res Notes
                BMC Res Notes
                BMC Research Notes
                BioMed Central (London )
                1756-0500
                18 September 2014
                18 September 2014
                2014
                : 7
                : 1
                Affiliations
                [ ]Department of Bioinformatics, College of Life Sciences, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga, Japan
                [ ]Japan Society for the Promotion of Science (JSPS) Research Fellow DC2, Tokyo, Japan
                Article
                3191
                10.1186/1756-0500-7-654
                4180342
                25231773
                © Matsuoka et al.; licensee BioMed Central Ltd. 2014

                This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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                © The Author(s) 2014

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