A robust methodology for inferring physiology of a protein family: application to K+-ion channel family

Abstract

We are interested in the subtle variations of function among the members of a protein family. A protein family is usually subdivided into subfamilies based on functional differences. Existence of this functional diversity is essential for the successful performance of physiological roles expected of the family. This presents a unique problem: there must be preservation of the active site; simultaneously there should be specificity of protein action according to subfamily. Though the classification into subfamilies is by no means a formalized one, it is most times based on the character of regulation of the primary function. The function of a subfamily is a modification of when the protein performs its function, for example, by changing the protein's sensitivity to regulatory factors. Rarely, a subfamily possesses a function completely different for its family. A study of these details is necessary for understanding the fine-tuning of protein function. I describe a theory for studying subfamily-based functional specificity and then validate it with an example application to deciphering the residue-level basis of fine functional variations in the diverse set of K+-channel subfamilies. I provide specific results that will be useful to channel physiologists, whereas the strategy developed will be widely applicable to problems in comparative and functional genomics.