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The structurally constrained protein evolution model accounts for sequence patterns of the LbetaH superfamily.

ABSTRACT: BACKGROUND: Structure conservation constrains evolutionary sequence divergence, resulting in observable sequence patterns. Most current models of protein evolution do not take structure into account explicitly, being unsuitable for investigating the effects of structure conservation on sequence divergence. To this end, we recently developed the Structurally Constrained Protein Evolution (SCPE) model. The model starts with the coding sequence of a protein with known three-dimensional structure. At each evolutionary time-step of an SCPE simulation, a trial sequence is generated by introducing a random point mutation in the current coding DNA sequence. Then, a "score" for the trial sequence is calculated and the mutation is accepted only if its score is under a given cutoff, lambda. The SCPE score measures the distance between the trial sequence and a given reference sequence, given the structure. In our first brief report we used a "global score", in which the same reference sequence, the ancestral one, was used at each evolutionary step. Here, we introduce a new scoring function, the "local score", in which the sequence accepted at the previous evolutionary time-step is used as the reference. We assess the model on the UDP-N-acetylglucosamine acyltransferase (LPXA) family, as in our previous report, and we extend this study to all other members of the left-handed parallel beta helix fold (LbetaH) superfamily whose structure has been determined. RESULTS: We studied site-dependent entropies, amino acid probability distributions, and substitution matrices predicted by SCPE and compared with experimental data for several members of the LbetaH superfamily. We also evaluated structure conservation during simulations. Overall, SCPE outperforms JTT in the description of sequence patterns observed in structurally constrained sites. Maximum Likelihood calculations show that the local-score and global-score SCPE substitution matrices obtained for LPXA outperform the JTT model for the LPXA family and for the structurally constrained sites of class i of other members within the LbetaH superfamily. CONCLUSION: We extended the SCPE model by introducing a new scoring function, the local score. We performed a thorough assessment of the SCPE model on the LPXA family and extended it to all other members of known structure of the LbetaH superfamily.

SUBMITTER: Parisi G

PROVIDER: S-EPMC538250 | biostudies-literature | 2004 Oct

REPOSITORIES: biostudies-literature

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The structurally constrained protein evolution model accounts for sequence patterns of the LbetaH superfamily.

Parisi Gustavo G Echave Julián J

BMC evolutionary biology 20041022

<h4>Background</h4>Structure conservation constrains evolutionary sequence divergence, resulting in observable sequence patterns. Most current models of protein evolution do not take structure into account explicitly, being unsuitable for investigating the effects of structure conservation on sequence divergence. To this end, we recently developed the Structurally Constrained Protein Evolution (SCPE) model. The model starts with the coding sequence of a protein with known three-dimensional struc ...[more]

PMID: 15500694

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Project description:The protein kinase family is large and important, but it is only one family in a larger superfamily of homologous kinases that phosphorylate a variety of substrates and play important roles in all three superkingdoms of life. We used a carefully constructed structural alignment of selected kinases as the basis for a study of the structural evolution of the protein kinase-like superfamily. The comparison of structures revealed a "universal core" domain consisting only of regions required for ATP binding and the phosphotransfer reaction. Remarkably, even within the universal core some kinase structures display notable changes, while still retaining essential activity. Hence, the protein kinase-like superfamily has undergone substantial structural and sequence revision over long evolutionary timescales. We constructed a phylogenetic tree for the superfamily using a novel approach that allowed for the combination of sequence and structure information into a unified quantitative analysis. When considered against the backdrop of species distribution and other metrics, our tree provides a compelling scenario for the development of the various kinase families from a shared common ancestor. We propose that most of the so-called "atypical kinases" are not intermittently derived from protein kinases, but rather diverged early in evolution to form a distinct phyletic group. Within the atypical kinases, the aminoglycoside and choline kinase families appear to share the closest relationship. These two families in turn appear to be the most closely related to the protein kinase family. In addition, our analysis suggests that the actin-fragmin kinase, an atypical protein kinase, is more closely related to the phosphoinositide-3 kinase family than to the protein kinase family. The two most divergent families, alpha-kinases and phosphatidylinositol phosphate kinases (PIPKs), appear to have distinct evolutionary histories. While the PIPKs probably have an evolutionary relationship with the rest of the kinase superfamily, the relationship appears to be very distant (and perhaps indirect). Conversely, the alpha-kinases appear to be an exception to the scenario of early divergence for the atypical kinases: they apparently arose relatively recently in eukaryotes. We present possible scenarios for the derivation of the alpha-kinases from an extant kinase fold.

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The structurally constrained protein evolution model accounts for sequence patterns of the LbetaH superfamily.

Publications

The structurally constrained protein evolution model accounts for sequence patterns of the LbetaH superfamily.

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