Binding constraints on the evolution of enzymes and signalling proteins: the important role of negative pleiotropy

• Published in: Proceedings of the Royal Society. B, Biological sciences Vol. 278; no. 1714; pp. 1930 - 1935
• Main Authors: Liberles, David A., Tisdell, Makayla D. M., Grahnen, Johan A.
• Format: Journal Article
• Language: English
• Published: England The Royal Society 07.07.2011
• Subjects: Amino Acid Substitution; Animals; Base Sequence; Bats; Binding Specificity; Chiroptera; Enzymes; Evolution; Evolution, Molecular; Genetic Pleiotropy; Genomes; Ligands; Molecular Evolution; Molecules; Pleiotropy; Population size; Protein Binding; Protein Folding; Review; Review Articles; Reviews; Sequence–structure–function Relationships; Signal Transduction; src Homology Domains; Substitution Rate; Vampires; Yeasts
• ISSN: 0962-8452; 1471-2945; 1471-2954
• DOI: 10.1098/rspb.2010.2637

A number of biophysical and population-genetic processes influence amino acid substitution rates. It is commonly recognized that proteins must fold into a native structure with preference over an unfolded state, and must bind to functional interacting partners favourably to function properly. What is less clear is how important folding and binding specificity are to amino acid substitution rates. A hypothesis of the importance of binding specificity in constraining sequence and functional evolution is presented. Examples include an evolutionary simulation of a population of SH2 sequences evolved by threading through the structure and binding to a native ligand, as well as SH3 domain signalling in yeast and selection for specificity in enzymatic reactions. An example in vampire bats where negative pleiotropy appears to have been adaptive is presented. Finally, considerations of compartmentalization and macromolecular crowding on negative pleiotropy are discussed.