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A tale of two ferredoxins: sequence similarity and structural differences.

ABSTRACT: Sequence similarity between proteins is usually considered a reliable indicator of homology. Pyruvate-ferredoxin oxidoreductase and quinol-fumarate reductase contain ferredoxin domains that bind [Fe-S] clusters and are involved in electron transport. Profile-based methods for sequence comparison, such as PSI-BLAST and HMMer, suggest statistically significant similarity between these domains.The sequence similarity between these ferredoxin domains resides in the area of the [Fe-S] cluster-binding sites. Although overall folds of these ferredoxins bear no obvious similarity, the regions of sequence similarity display a remarkable local structural similarity. These short regions with pronounced sequence motifs are incorporated in completely different structural environments. In pyruvate-ferredoxin oxidoreductase (bacterial ferredoxin), the hydrophobic core of the domain is completed by two beta-hairpins, whereas in quinol-fumarate reductase (alpha-helical ferredoxin), the cluster-binding motifs are part of a larger all-alpha-helical globin-like fold core.Functionally meaningful sequence similarity may sometimes be reflected only in local structural similarity, but not in global fold similarity. If detected and used naively, such similarities may lead to incorrect fold predictions.

SUBMITTER: Krishna SS

PROVIDER: S-EPMC1459171 | biostudies-literature | 2006 Apr

REPOSITORIES: biostudies-literature

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A tale of two ferredoxins: sequence similarity and structural differences.

Krishna S Sri SS Sadreyev Ruslan I RI Grishin Nick V NV

BMC structural biology 20060409

<h4>Background</h4>Sequence similarity between proteins is usually considered a reliable indicator of homology. Pyruvate-ferredoxin oxidoreductase and quinol-fumarate reductase contain ferredoxin domains that bind [Fe-S] clusters and are involved in electron transport. Profile-based methods for sequence comparison, such as PSI-BLAST and HMMer, suggest statistically significant similarity between these domains.<h4>Results</h4>The sequence similarity between these ferredoxin domains resides in the ...[more]

PMID: 16603087

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Project description:BACKGROUND: It has been previously shown that palindromic sequences are frequently observed in proteins. However, our knowledge about their evolutionary origin and their possible importance is incomplete. RESULTS: In this work, we tried to revisit this relatively neglected phenomenon. Several questions are addressed in this work. (1) It is known that there is a large chance of finding a palindrome in low complexity sequences (i.e. sequences with extreme amino acid usage bias). What is the role of sequence complexity in the evolution of palindromic sequences in proteins? (2) Do palindromes coincide with conserved protein sequences? If yes, what are the functions of these conserved segments? (3) In case of conserved palindromes, is it always the case that the whole conserved pattern is also symmetrical? (4) Do palindromic protein sequences form regular secondary structures? (5) Does sequence similarity of the two "sides" of a palindrome imply structural similarity? For the first question, we showed that the complexity of palindromic peptides is significantly lower than randomly generated palindromes. Therefore, one can say that palindromes occur frequently in low complexity protein segments, without necessarily having a defined function or forming a special structure. Nevertheless, this does not rule out the possibility of finding palindromes which play some roles in protein structure and function. In fact, we found several palindromes that overlap with conserved protein Blocks of different functions. However, in many cases we failed to find any symmetry in the conserved regions of corresponding Blocks. Furthermore, to answer the last two questions, the structural characteristics of palindromes were studied. It is shown that palindromes may have a great propensity to form alpha-helical structures. Finally, we demonstrated that the two sides of a palindrome generally do not show significant structural similarities. CONCLUSION: We suggest that the puzzling abundance of palindromic sequences in proteins is mainly due to their frequent concurrence with low-complexity protein regions, rather than a global role in the protein function. In addition, palindromic sequences show a relatively high tendency to form helices, which might play an important role in the evolution of proteins that contain palindromes. Moreover, reverse similarity in peptides does not necessarily imply significant structural similarity. This observation rules out the importance of palindromes for forming symmetrical structures. Although palindromes frequently overlap with conserved Blocks, we suggest that palindromes overlap with Blocks only by coincidence, rather than being involved with a certain structural fold or protein domain.

Project description:BACKGROUND:Despite sharing 92% sequence identity, paralogous human translation elongation factor 1 alpha-1 (eEF1A1) and elongation factor 1 alpha-2 (eEF1A2) have different but overlapping functional profiles. This may reflect the differential requirements of the cell-types in which they are expressed and is consistent with complex roles for these proteins that extend beyond delivery of tRNA to the ribosome. METHODOLOGY/PRINCIPAL FINDINGS:To investigate the structural basis of these functional differences, we created and validated comparative three-dimensional (3-D) models of eEF1A1 and eEF1A2 on the basis of the crystal structure of homologous eEF1A from yeast. The spatial location of amino acid residues that vary between the two proteins was thereby pinpointed, and their surface electrostatic and lipophilic properties were compared. None of the variations amongst buried amino acid residues are judged likely to have a major structural effect on the protein fold, or to affect domain-domain interactions. Nearly all the variant surface-exposed amino acid residues lie on one face of the protein, in two proximal but distinct sub-clusters. The result of previously performed mutagenesis in yeast may be interpreted as confirming the importance of one of these clusters in actin-bundling and filament disorganization. Interestingly, some variant residues lie in close proximity to, and in a few cases show differences in interactions with, residues previously inferred to be directly involved in binding GTP/GDP, eEF1Balpha and aminoacyl-tRNA. Additional sequence-based predictions, in conjunction with the 3-D models, reveal likely differences in phosphorylation sites that could reconcile some of the functional differences between the two proteins. CONCLUSIONS:The revelation and putative functional assignment of two distinct sub-clusters on the surface of the protein models should enable rational site-directed mutagenesis, including homologous reverse-substitution experiments, to map surface binding patches onto these proteins. The predicted variant-specific phosphorylation sites also provide a basis for experimental verification by mutagenesis. The models provide a structural framework for interpretation of the resulting functional analysis.

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A tale of two ferredoxins: sequence similarity and structural differences.

Publications

A tale of two ferredoxins: sequence similarity and structural differences.

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