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Sequence variations within protein families are linearly related to structural variations.

ABSTRACT: It is commonly believed that similarities between the sequences of two proteins infer similarities between their structures. Sequence alignments reliably recognize pairs of protein of similar structures provided that the percentage sequence identity between their two sequences is sufficiently high. This distinction, however, is statistically less reliable when the percentage sequence identity is lower than 30% and little is known then about the detailed relationship between the two measures of similarity. Here, we investigate the inverse correlation between structural similarity and sequence similarity on 12 protein structure families. We define the structure similarity between two proteins as the cRMS distance between their structures. The sequence similarity for a pair of proteins is measured as the mean distance between the sequences in the subsets of sequence space compatible with their structures. We obtain an approximation of the sequence space compatible with a protein by designing a collection of protein sequences both stable and specific to the structure of that protein. Using these measures of sequence and structure similarities, we find that structural changes within a protein family are linearly related to changes in sequence similarity.

SUBMITTER: Koehl P

PROVIDER: S-EPMC2692051 | biostudies-literature | 2002 Oct

REPOSITORIES: biostudies-literature

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Sequence variations within protein families are linearly related to structural variations.

Koehl Patrice P Levitt Michael M

Journal of molecular biology 20021001 3

It is commonly believed that similarities between the sequences of two proteins infer similarities between their structures. Sequence alignments reliably recognize pairs of protein of similar structures provided that the percentage sequence identity between their two sequences is sufficiently high. This distinction, however, is statistically less reliable when the percentage sequence identity is lower than 30% and little is known then about the detailed relationship between the two measures of s ...[more]

PMID: 12381308

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Project description:Craniosynostosis refers to a condition during early development in which one or more of the fibrous sutures of the skull prematurely fuse by turning into bone, which produces recognizable patterns of cranial shape malformations depending on which suture(s) are affected. In addition to cases with isolated cranial dysmorphologies, craniosynostosis appears in syndromes that include skeletal features of the eyes, nose, palate, hands, and feet as well as impairment of vision, hearing, and intellectual development. Approximately 85% of the cases are nonsyndromic sporadic and emerge after de novo structural genome rearrangements or single nucleotide variation, while the remainders consist of syndromic cases following mendelian inheritance. By karyotyping, genome wide linkage, and CNV analyses as well as by whole exome and whole genome sequencing, numerous candidate genes for craniosynostosis belonging to the FGF, Wnt, BMP, Ras/ERK, ephrin, hedgehog, STAT, and retinoic acid signaling pathways have been identified. Many of the craniosynostosis-related candidate genes form a functional network based upon protein-protein or protein-DNA interactions. Depending on which node of this craniosynostosis-related network is affected by a gene mutation or a change in gene expression pattern, a distinct craniosynostosis syndrome or set of phenotypes ensues. Structural variations may alter the dosage of one or several genes or disrupt the genomic architecture of genes and their regulatory elements within topologically associated chromatin domains. These may exert dominant effects by either haploinsufficiency, dominant negative partial loss of function, gain of function, epistatic interaction, or alteration of levels and patterns of gene expression during development. Molecular mechanisms of dominant modes of action of these mutations may include loss of one or several binding sites for cognate protein partners or transcription factor binding sequences. Such losses affect interactions within functional networks governing development and consequently result in phenotypes such as craniosynostosis. Many of the novel variants identified by genome wide CNV analyses, whole exome and whole genome sequencing are incorporated in recently developed diagnostic algorithms for craniosynostosis.

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Sequence variations within protein families are linearly related to structural variations.

Publications

Sequence variations within protein families are linearly related to structural variations.

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