MBE Advance Access published online on August 13, 2008
Molecular Biology and Evolution, doi:10.1093/molbev/msn179
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Research Article |
Evolution of snake venom disintegrins by positive darwinian selection
1 Instituto de Biomedicina de Valencia, CSIC, Jaime Roig 11, 46010 Valencia, Spain
2 Instituto Cavanilles de Biodiversidad y Biología Evolutiva, Universidad de Valencia, Polígono La Coma s/n, 46071 Valencia, Spain
3 CIBER en Epidemiología y Salud Pública (CIBERESP), Valencia, Spain
Correspondence to: Juan J. Calvete, Instituto de Biomedicina de Valencia, C.S.I.C., Jaime Roig 11, 46010 Valencia, Spain; Tel: +34 96 339 1778; Fax: +34 96 369 0800; E.mail: jcalvete{at}ibv.csic.es
Received for publication April 22, 2008. Revision received July 15, 2008. Revision received August 7, 2008. Accepted for publication August 8, 2008.
PII disintegrins, cysteine-rich polypeptides broadly distributed in the venoms of geographically diverse species of vipers and rattlesnakes, antagonize the adhesive functions of β1 and β3 integrin receptors. PII disintegrins evolved in Viperidae by neofunctionalization of disintegrin-like domains of duplicated PIII-SVMP genes recruited into the venom proteome before the radiation of the advanced snakes. Minimization of the gene (loss of introns and coding regions) and the protein structures (successive loss of disulfide bonds) underpin the post-duplication divergence of disintegrins. However, little is known about the underlying genetic mechanisms that has generated the structural and functional diversity among disintegrins. Phylogenetic inference and maximum likelihood-based codon substitution approaches were used to analyze the evolution of the disintegrin family. The topology of the phylogenetic tree does not paralell that of the species tree. This incongruence is consistent with that expected for a multigene family undergoing a birth-and-death process in which the appearance and disappearance of loci are being driven by selection. Cysteine and buried residues appear to be under strong purifying selection due to their role in maintaining the active conformation of disintegrins. Divergence of disintegrins is strongly influenced by positive Darwinian selection causing accelerated rate of substitution in a substantial proportion of surface-exposed disintegrin residues. Global and lineage-specific sites evolving under diversifying selection were identified. Several sites are located within the integrin-binding loop and the C-terminal tail, two regions which form a conformational functional epitope. RGD was inferred to represent the ancestral integrin-recognition motif, which emerged from the subgroup of PIII-SVMPs bearing the RDECD sequence. The most parsimonious nucleotide substitution model required for the emergence of all known disintegrin's integrin inhibitory motifs from an ancestral RGD sequence involves a minimum of three mutations. The adaptive advantage of the emergence of motifs targeting β1 integrins, and the role of positively selected sites located within nonfunctional disintegrin regions appear to be difficult to rationalize in the context of a predator-prey arms race. Perhaps this represents a consequence of the neofunctionalization potential of the disintegrin domain, a feature which may underlie its recruitment into the venom proteome followed by its successful transformation into a toxin.
Key Words: Molecular evolution • snake venom disintegrins • adaptive evolution • positive Darwinian selection • phylogeny
* These authors contributed equally to this work and may both be considered first authors.