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At least 379 records · Page 21Linked to original sources
PubMed2002

Identification of residues in glutathione transferase capable of driving functional diversification in evolution. A novel approach to protein redesign.

Evolution of protein function can be driven by positive selection of advantageous nonsynonymous codon mutations that arise following gene duplication. By observing the presence and degree of site-specific positive selection for change between divergent paralogs, residue positions responsible for functional changes can be identified. We applied this analysis to genes encoding Mu class glutathione transferases, which differ widely in substrate specificities. Approximately 3% of the amino acid residue positions, both near to and distant from the active site, are under statistically significant positive selection for change. Relevant human glutathione transferase (GST) M1-1 and GST M2-2 codons were mutated. A chemically conservative threonine to serine mutation in GST M2-2 elicited a 1,000-fold increase in specific activity with the GST M1-1-specific substrate trans-stilbene oxide and a 30-fold increase with the alternative epoxide substrates styrene oxide and nitrophenyl glycidol. The reverse mutation in GST M1-1 resulted in reciprocal decreases in activity. Thus, identification of hypervariable codon positions can be a powerful aid in the redesign of protein function, lessening the requirement for extensive mutagenesis or structural knowledge and sometimes suggesting mutations that would otherwise be considered functionally conservative.

Evolution, Molecular↗
PubMed2006

Graph theoretical insights into evolution of multidomain proteins.

We study properties of multidomain proteins from a graph theoretical perspective. In particular, we demonstrate connections between properties of the domain overlap graph and certain variants of Dollo parsimony models. We apply our graph theoretical results to address several interrelated questions: do proteins acquire new domains infrequently, or often enough that the same combinations of domains will be created repeatedly through independent events? Once domain architectures are created do they persist? In other words, is the existence of ancestral proteins with domain compositions not observed in contemporary proteins unlikely? Our experimental results indicate that independent merges of domain pairs are not uncommon in large superfamilies.

Amino Acids↗
PubMed1997

Homology modelling of the catalytic domain of early mammalian protein C: evolution of structural features.

By means of a novel cDNA-based strategy employing the maximum parsimony principle, we have previously deduced probable amino acid sequences for the catalytic domains of the early mammalian ancestors of each of the five extant vitamin K-dependent serine proteases of coagulation, and for their common ancestor from a still earlier stage of vertebrate evolution. In the present study, we employed one of these sequences to construct a molecular model of the catalytic domain of early mammalian protein C and to explore its functional architecture. Following the domain's progression from the common ancestor of the vitamin K-dependent serine proteases toward extant human protein C, this novel application of homology modelling to a reconstructed amino acid sequence has allowed us to trace the evolution of structural features in a vital coagulation protein.

Amino Acid Sequence↗
PubMed2000

Molecular evolution in a multisite nearly neutral mutation model.

A simple nearly neutral mutation model of protein evolution was studied using computer simulation assuming a constant population size. In this model, a gene consists of a finite number of codons and there is no recombination within a gene. Each codon has two replacement and one silent sites. The fitness of a gene was determined multiplicatively by amino acids specified by codons (the independent multicodon model). Nucleotide diversity at replacement sites decreases as selection becomes stronger. A reduction of nucleotide diversity at silent sites also occurs as selection intensifies but the magnitude of the reduction is not a monotone function of the intensity of selection. The dispersion index is close to one. The average value of Tajima's and Fu and Li's statistics are negative and their absolute values increases as selection intensifies. However, their powers of detecting selection under the present model were not high unless the number of sites is large or mutation rate is high. The MK test was shown to detect intermediate selection fairly well. For comparison, the house-of-cards model was also investigated and its behavior was shown to be more sensitive to changes of population size than that of the independent multicodon model. The relevance of the present model for explaining protein evolution was discussed comparing its prediction and recent DNA data.

Amino Acid Substitution↗
PubMed2001

NIFAS: visual analysis of domain evolution in proteins.

MOTIVATION: Multi-domain proteins have evolved by insertions or deletions of distinct protein domains. Tracing the history of a certain domain combination can be important for functional annotation of multi-domain proteins, and for understanding the function of individual domains. In order to analyze the evolutionary history of the domains in modular proteins it is desirable to inspect a phylogenetic tree based on sequence divergence with the modular architecture of the sequences superimposed on the tree. RESULT: A Java applet, NIFAS, that integrates graphical domain schematics for each sequence in an evolutionary tree was developed. NIFAS retrieves domain information from the Pfam database and uses CLUSTAL W to calculate a tree for a given Pfam domain. The tree can be displayed with symbolic bootstrap values, and to allow the user to focus on a part of the tree, the layout can be altered by swapping nodes, changing the outgroup, and showing/collapsing subtrees. NIFAS is integrated with the Pfam database and is accessible over the internet (http://www.cgr.ki.se/Pfam). As an example, we use NIFAS to analyze the evolution of domains in Protein Kinases C.

Computer Graphics↗
PubMed2006

Ancient origin of reggie (flotillin), reggie-like, and other lipid-raft proteins: convergent evolution of the SPFH domain.

Reggies (flotillins) are detergent-resistant microdomains involved in the scaffolding of large heteromeric complexes that signal across the plasma membrane. Based on the presence of an evolutionarily widespread motif, reggies/flotillins have been included within the SPFH (stomatin-prohibitin-flotillin-HflC/K) protein superfamily. To better understand the origin and evolution of reggie/flotillin structure and function, we searched databases for reggie/flotillin and SPFH-like proteins in organisms at the base and beyond the animal kingdom, and used the resulting dataset to compare their structural and functional domains. Our analysis shows that the SPFH grouping has little phylogenetic support, probably due to convergent evolution of its members. We also find that reggie/flotillin homologues are highly conserved among metazoans but are absent in plants, fungi and bacteria, where only proteins with "reggie-like" domains can be found. However, despite their low sequence similarities, reggie/flotillin and "reggie-like" domains appear to subserve related functions, suggesting that their basic biological role was acquired independently during evolution.

Amino Acid Sequence↗
PubMed1993

Empirical and structural models for insertions and deletions in the divergent evolution of proteins.

The exhaustive matching of the protein sequence database makes possible a broadly based study of insertions and deletions (indels) during divergent evolution. In this study, the probability of a gap in an alignment of a pair of homologous protein sequences was found to increase with the evolutionary distance measured in PAM units (number of accepted point mutations per 100 amino acid residues). A relationship between the average number of amino acid residues between indels and evolutionary distance suggests that a unit 30 to 40 amino acid residues in length remains, on average, undisrupted by indels during divergent evolution. Further, the probability of a gap was found to be inversely proportional to gap length raised to the 1.7 power. This empirical law fits closely over the entire range of gap lengths examined. Gap length distribution is largely independent of evolutionary distance. These results rule out the widely used linear gap penalty as a satisfactory formula for scoring gaps when constructing alignments. Further, the observed gap length distribution can be explained by a simple model of selective pressures governing the acceptance of indels during divergent evolution. Finally, this model provides theoretical support for using indels as part of "parsing algorithms", important in the de novo prediction of the folded structure of proteins from the sequence data.

Amino Acid Sequence↗
PubMed1996

Exploring the functional robustness of an enzyme by in vitro evolution.

The evolution of natural proteins is thought to have occurred by successive fixation of individual mutations. In vitro protein evolution seeks to accelerate this process. RNA hypermutagenesis, cDNA synthesis in the presence of biased dNTP concentrations, delivers elevated mutant and mutation frequencies. Here lineages of active enzymes descended from the homotetrameric 78 residue dihydrofolate reductase (DHFR) encoded by the Escherichia coli R67 plasmid were generated by iterative RNA hypermutagenesis, resulting in >20% amino acid replacement. The 22 residue N-terminus could be deleted yielding a minimum functional entity refractory to further changes, designating it as a determinant of R67 robustness. Complete substitution of the segment still allowed fixation of mutations. By the facile introduction of multiple mutations, RNA hypermutagenesis allows the generation of active proteins derived from extant genes through a mode unexplored by natural selection.

Amino Acid Sequence↗
PubMed1983

The structural conservation of S100 protein during evolution: analysis by reactivity with a monoclonal antibody.

A hybridoma cell line producing a monoclonal antibody (A4) against bovine S100 protein has been produced by fusing mouse myeloma P3X63/Ag8 cells with spleen cells from a BALB/c mouse immunized with bovine S100 protein. A4 is of the IgG2b subclass and was purified by affinity chromatography on a protein A-Sepharose column. Brain extracts from several mammalian and one avian species reacted both with polyclonal rabbit anti-S100 protein antiserum and with A4 in a radioimmunoassay. Brain extract from dog was a notable exception. It reacted with the rabbit antiserum but not with A4. Therefore A4 reacts with a common epitope that is present on S100 proteins from different vertebrate species but is absent on dog S100 protein.

Animals↗
PubMed2005

Divergent evolution within protein superfolds inferred from profile-based phylogenetics.

Many dissimilar protein sequences fold into similar structures. A central and persistent challenge facing protein structural analysis is the discrimination between homology and convergence for structurally similar domains that lack significant sequence similarity. Classic examples are the OB-fold and SH3 domains, both small, modular beta-barrel protein superfolds. The similarities among these domains have variously been attributed to common descent or to convergent evolution. Using a sequence profile-based phylogenetic technique, we analyzed all structurally characterized OB-fold, SH3, and PDZ domains with less than 40% mutual sequence identity. An all-against-all, profile-versus-profile analysis of these domains revealed many previously undetectable significant interrelationships. The matrices of scores were used to infer phylogenies based on our derivation of the relationships between sequence similarity E-values and evolutionary distances. The resulting clades of domains correlate remarkably well with biological function, as opposed to structural similarity, indicating that the functionally distinct sub-families within these superfolds are homologous. This method extends phylogenetics into the challenging "twilight zone" of sequence similarity, providing the first objective resolution of deep evolutionary relationships among distant protein families.

Evolution, Molecular↗
PubMed1978

The evolution of protein sequences by repetitious gene duplication: clostridial flavodoxin.

Internal regularities of amino acid sequences of flavodoxins, FMN-containing, low molecular weight flavoproteins, were statistically examined using the minimum mutation method. The sequence of Clostridium pasteurianum flavodoxin shows statistically significant evidence of repetitious internal gene duplications at different levels of structure. Peptide pairs with a low chance probabilitiy of occurrence were frequently observed at a shift of 5 residues. The pairs with the lowest chance probabilities are a pair of heptapeptides at positions39--45 vs. 44--50, a 5 residue shift (p = 9 x 10(-6)). Most of the related pairs are consistent and could best be explained by the repeating pentapeptide sequence: (Lys-Gly-Ala-Asp-Val-)n and appropriate gaps. Internal repetitions with longer shifts were also suggested for other flavodoxins. Repetitious gene duplication is proposed for the early stages of flavodoxin evolution.

Amino Acid Sequence↗
PubMed1998

Mechanism and evolution of protein dimerization.

We have investigated the mechanism and the evolutionary pathway of protein dimerization through analysis of experimental structures of dimers. We propose that the evolution of dimers may have multiple pathways, including (1) formation of a functional dimer directly without going through an ancestor monomer, (2) formation of a stable monomer as an intermediate followed by mutations of its surface residues, and (3), a domain swapping mechanism, replacing one segment in a monomer by an equivalent segment from an identical chain in the dimer. Some of the dimers which are governed by a domain swapping mechanism may have evolved at an earlier stage of evolution via the second mechanism. Here, we follow the theory that the kinetic pathway reflects the evolutionary pathway. We analyze the structure-kinetics-evolution relationship for a collection of symmetric homodimers classified into three groups: (1) 14 dimers, which were referred to as domain swapping dimers in the literature; (2) nine 2-state dimers, which have no measurable intermediates in equilibrium denaturation; and (3), eight 3-state dimers, which have stable intermediates in equilibrium denaturation. The analysis consists of the following stages: (i) The dimer is divided into two structural units, which have twofold symmetry. Each unit contains a contiguous segment from one polypeptide chain of the dimer, and its complementary contiguous segment from the other chain. (ii) The division is repeated progressively, with different combinations of the two segments in each unit. (iii) The coefficient of compactness is calculated for the units in all divisions. The coefficients obtained for different cuttings of a dimer form a compactness profile. The profile probes the structural organization of the two chains in a dimer and the stability of the monomeric state. We describe the features of the compactness profiles in each of the three dimer groups. The profiles identify the swapping segments in domain swapping dimers, and can usually predict whether a dimer has domain swapping. The kinetics of dimerization indicates that some dimers which have been assigned in the literature as domain swapping cases, dimerize through the 2-state kinetics, rather than through swapping segments of performed monomers. The compactness profiles indicate a wide spectrum in the kinetics of dimerization: dimers having no intermediate stable monomers; dimers having an intermediate with a stable monomer structure; and dimers having an intermediate with a stable structure in part of the monomer. These correspond to the multiple evolutionary pathways for dimer formation. The evolutionary mechanisms proposed here for dimers are applicable to other oligomers as well.

Biological Evolution↗
PubMed1979

Origins of metabolic diversity: evolutionary divergence by sequence repetition.

Recurring patterns of primary structure have been observed in enzymes that mediate sequential metabolic reactions in bacteria. The enzymes, muconolactone Delta-isomerase [(+)-4-hydroxy-4-carboxymethylisocrotonolactone Delta(2)-Delta(3)-isomerase, EC 5.3.3.4] and beta-ketoadipate enol-lactone hydrolase [4-carboxymethylbut-3-enolide(1,4)enol-lactone-hydrolase, EC 3.1.1.24], have been coselected in bacterial populations because the isomerase can confer no nutritional advantage in the absence of the hydrolase. Similar amino acid sequences recur within the structure of the isomerase, and the amino-terminal amino acid sequence of the isomerase from Pseudomonas putida appears to be evolutionarily homologous with the corresponding sequence of a beta-ketoadipate enol-lactone hydrolase from Acinetobacter calcoaceticus. One interpretation of the sequence repetitions is that they reflect tandem duplication mutations that took place early in the evolution of the proteins. According to this view, the mutations caused elongation of structural genes and the creation of duplicated genes as the metabolic pathways evolved. A review of the sequence data calls attention to a different hypothesis: repeated amino acid sequences were introduced in the course of the proteins' evolution by substitution of copies of DNA sequences into structural genes. Our observations are interpreted on the basis of a model proposing genetic exchange between misaligned DNA sequences. The model predicts that misalignments in one chromosomal region can influence the nature of mutations in another region. Thus, as often has been observed, the mutability of a base pair will be determined by its location in a DNA sequence. Furthermore, the intrachromosomal recombination of DNA sequences may account for complex genetic modifications that occur as new pathways evolve. The model provides an interpretation of an apparent paradox, the rapid creation of new metabolic traits by bacterial genomes that are remarkably resistant to genetic drift.

Amino Acid Sequence↗
PubMed2002

Determining the roles of different chain fragments in recognition of immunoglobulin fold.

We examine sequence-to-structure specificity of beta-structural fragments of immunoglobulin domains. The structure specificity of separate chain fragments is estimated by computing the Z-score values in recognition of the native structure in gapless threading tests. To improve the accuracy of our calculations we use energy averaging over diverse homologs of immunoglobulin domains. We show that the interactions between residues of beta-structure are more determinant in recognition of the native structure than the interactions within the whole chain molecule. This result distinguishes immunoglobulins from more typical proteins where the interactions between residues of the whole chain normally recognize the native fold more accurately than interactions between the residues of the secondary structure residues alone [Reva,B. and Topiol,S. (2000) BIOCOMPUTING: Proceedings of the Pacific Symposium. World Scientific Publishing Co., pp. 168-178]. We also find that the predominant contributions of the secondary structure are produced by the four central beta-strands that form the core of the molecule. The results of this study allow us through quantitative means to understand the architecture of immunoglobulin molecules. Comparing the fold recognition data for different chain fragments one can say that beta-strands form a rigid frame for immunoglobulin molecules, whereas loops, with no structural role, can develop a broad variety of binding specificities. It is well known that protein function is determined by specific portions of a protein chain. This study suggests that the whole protein structure can be predominantly determined by a few fragments of chain which form the structural framework of the molecule. This idea may help in better understanding the mechanisms of protein evolution: strengthening a protein structure in the key framework-forming regions allows mutations and flexibility in other chain regions.

Amino Acid Sequence↗