A method to recognize distant repeats in protein sequences

An automated algorithm is presented that delineates protein sequence fragments which display similarity. The method incorporates a selection of a number of local nonoverlapping sequence alignments with the highest similarity scores and a graphtheoretical approach to elucidate the consistent start and end points of the fragments comprising one or more ensembles of related subsequences. The procedure allows the simultaneous identification of different types of repeats within one sequence. A multiple alignment of the resulting fragments is performed and a consensus sequence derived from the ensemble(s). Finally, a profile is constructed form the multiple alignment to detect possible and more distant members within the sequence. The method tolerates mutations in the repeats as well as insertions and deletions. The sequence spans between the various repeats or repeat clusters may be of different lengths. The technique has been applied to a number of proteins where the repeating fragments have been derived from information additional to the protein sequences. © 1993 Wiley-Liss, Inc.     

Intron/exon structure of the human gene for the muscle isozyme of glycogen phosphorylase

The intron/exon organization of the human gene for glycogen phosphorylase has been determined. The segments of the polypeptide chain that corresponds to the 19 exons of the gene are examined for relationships between the three-dimensional structure to the protein and gene structure. Only weak correlations are observed between domains of phosphorylase and exons. The nucleotide binding domains that are found in phosphorylase and other glycolytic enzymes are examined for relationships between exons of the genes and structures of the domains. When mapped to the three-dimensional structures, the intron/exon boundaries are shown to be widely distributed in this family of protein domains.     

Evolutionary analysis of amino acid repeats across the genomes of 12 Drosophila species

Repeated motifs of amino acids within proteins are an abundant feature of eukaryotic sequences and may catalyze the rapid production of genetic and even phenotypic variation among organisms. The completion of the genome sequencing projects of 12 distinct Drosophila species provides a unique dataset to study these intriguing sequence features on a phylogeny with a variety of timescales. We show that there is a higher percentage of proteins containing repeats within the Drosophila genus than most other eukaryotes, including non-Drosphila insects, which makes this collection of species particularly useful for the study of protein repeats. We also find that proteins containing repeats are overrepresented in functional categories involving developmental processes, signaling, and gene regulation. Using the set of 1-to-1 ortholog alignments for the 12 Drosophila species, we test the ability of repeats to act as reliable phylogenetic signals and find that they resolve the generally accepted phylogeny despite the noise caused by their accelerated rate of evolution. We also determine that in general the position of repeats within a protein sequence is non-random, with repeats more often being absent from the middle regions of sequences. Finally we find evidence to suggest that the presence of repeats is associated with an increase in evolutionary rate upon the entire sequence in which they are embedded. With additional evidence to suggest a corresponding elevation in positive selection we propose that some repeats may be inducing compensatory substitutions in their surrounding sequence.     

水稻锚蛋白基因家族分析和锚定膜蛋白的表达模式研究

锚蛋白重复序列模体是生物体内最普遍的蛋白质序列模体之一,在多种细胞活动中主要介导蛋白质与蛋白质的相互作用。采用生物信息学的方法,在基因组水平上搜索和鉴定了水稻锚定重复序列蛋白,通过分析蛋白质二级结构,进行水稻锚蛋白基因家族的聚类分析,并在此基础上,用RT-PCR的方法分析水稻锚定膜蛋白的表达模式,为水稻锚蛋白基因的研究提供了理论依据。     

High conservation of the trinucleotide [CTG]n repeat at the myotonic dystrophy locus in nonhuman primates

Myotonic dystrophy is due to instability of a [CTG] repeat in the myotonin-protein kinase gene. We have sequenced the complete 3′ untranslated region of this gene which contains the repeat, in seven nonhuman primates. We found that the genomic organisation was conserved, suggesting that this region has important regulatory functions. These data also argue that the human state is derived from a primate ancestor in which the mutational event did not involve the loss of cryptic sequences interrupting or surrounding the repeat, but likely affected only the original length of the repeat.     

Recapitulation of protein family divergence using flexible backbone protein design

We use flexible backbone protein design to explore the sequence and structure neighborhoods of naturally occurring proteins. The method samples sequence and structure space in the vicinity of a known sequence and structure by alternately optimizing the sequence for a fixed protein backbone using rotamer based sequence search, and optimizing the backbone for a fixed amino acid sequence using atomic-resolution structure prediction. We find that such a flexible backbone design method better recapitulates protein family sequence variation than sequence optimization on fixed backbones or randomly perturbed backbone ensembles for ten diverse protein structures. For the SH3 domain, the backbone structure variation in the family is also better recapitulated than in randomly perturbed backbones. The potential application of this method as a model of protein family evolution is highlighted by a concerted transition to the amino acid sequence in the structural core of one SH3 domain starting from the backbone coordinates of an homologous structure.     

Sequence optimization for native state stability determines the evolution and folding kinetics of a small protein

Investigating the relative importance of protein stability, function, and folding kinetics in driving protein evolution has long been hindered by the fact that we can only compare modern natural proteins, the products of the very process we seek to understand, to each other, with no external references or baselines. Through a large-scale all-atom simulation of protein evolution, we have created a large diverse alignment of SH3 domain sequences which have been selected only for native state stability, with no other influencing factors. Although the average pairwise identity between computationally evolved and natural sequences is only 17%, the residue frequency distributions of the computationally evolved sequences are similar to natural SH3 sequences at 86% of the positions in the domain, suggesting that optimization for the native state structure has dominated the evolution of natural SH3 domains. Additionally, the positions which play a consistent role in the transition state of three well-characterized SH3 domains (by phi-value analysis) are structurally optimized for the native state, and vice versa. Indeed, we see a specific and significant correlation between sequence optimization for native state stability and conservation of transition state structure.     

FAIR: A server for internal sequence repeats

An Internet computing server has been developed to identify all the occurrences of the internal sequence repeats in a protein and DNA sequences. Further, an option is provided for the users to check the occurrence(s) of the resultant sequence repeats in the other sequence and structure (Protein Data Bank) databases. The databases deployed in the proposed computing engine are up-to-date and thus the users will get the latest information available in the respective databases. The server is freely accessible over the World Wide Web (WWW). AVAILABILITY: http://bioserver1.physics.iisc.ernet.in/fair/     

Some Probabilistic Results on the Nonrandomness of Simple Sequence Repeats in DNA Sequences

Some probabilistic results on simple sequence repeats (SSRs) in DNA sequences are derived and used to quantify the nonrandomness of SSRs as an index of nonrandomness. The applicability of the index of nonrandomness is illustrated using several examples from the literature on selected human diseased genes.     

Conservation of inter-residue interactions and prediction of folding rates of domain repeats

Domains are the main structural and functional units of larger proteins. They tend to be contiguous in primary structure and can fold and function independently. It has been observed that 10–20% of all encoded proteins contain duplicated domains and the average pairwise sequence identity between them is usually low. In the present study, we have analyzed the structural similarity between domain repeats of proteins with known structures available in the Protein Data Bank using structure-based inter-residue interaction measures such as the number of long-range contacts, surrounding hydrophobicity, and pairwise interaction energy. We used RADAR program for detecting the repeats in a protein sequence which were further validated using Pfam domain assignments. The sequence identity between the repeats in domains ranges from 20 to 40% and their secondary structural elements are well conserved. The number of long-range contacts, surrounding hydrophobicity calculations and pairwise interaction energy of the domain repeats clearly reveal the conservation of 3-D structure environment in the repeats of domains. The proportions of mainchain–mainchain hydrogen bonds and hydrophobic interactions are also highly conserved between the repeats. The present study has suggested that the computation of these structure-based parameters will give better clues about the tertiary environment of the repeats in domains. The folding rates of individual domains in the repeats predicted using the long-range order parameter indicate that the predicted folding rates correlate well with most of the experimentally observed folding rates for the analyzed independently folded domains.     

The architectural design of networks of protein domain architectures

Protein domain architectures (PDAs), in which single domains are linked to form multiple-domain proteins, are a major molecular form used by evolution for the diversification of protein functions. However, the design principles of PDAs remain largely uninvestigated. In this study, we constructed networks to connect domain architectures that had grown out from the same single domain for every single domain in the Pfam-A database and found that there are three main distinctive types of these networks, which suggests that evolution can exploit PDAs in three different ways. Further analysis showed that these three different types of PDA networks are each adopted by different types of protein domains, although many networks exhibit the characteristics of more than one of the three types. Our results shed light on nature''s blueprint for protein architecture and provide a framework for understanding architectural design from a network perspective.     

Modeling the evolution of protein domain architectures using maximum parsimony

Domains are basic evolutionary units of proteins and most proteins have more than one domain. Advances in domain modeling and collection are making it possible to annotate a large fraction of known protein sequences by a linear ordering of their domains, yielding their architecture. Protein domain architectures link evolutionarily related proteins and underscore their shared functions. Here, we attempt to better understand this association by identifying the evolutionary pathways by which extant architectures may have evolved. We propose a model of evolution in which architectures arise through rearrangements of inferred precursor architectures and acquisition of new domains. These pathways are ranked using a parsimony principle, whereby scenarios requiring the fewest number of independent recombination events, namely fission and fusion operations, are assumed to be more likely. Using a data set of domain architectures present in 159 proteomes that represent all three major branches of the tree of life allows us to estimate the history of over 85% of all architectures in the sequence database. We find that the distribution of rearrangement classes is robust with respect to alternative parsimony rules for inferring the presence of precursor architectures in ancestral species. Analyzing the most parsimonious pathways, we find 87% of architectures to gain complexity over time through simple changes, among which fusion events account for 5.6 times as many architectures as fission. Our results may be used to compute domain architecture similarities, for example, based on the number of historical recombination events separating them. Domain architecture "neighbors" identified in this way may lead to new insights about the evolution of protein function.