Evolutionary Use of Domain Recombination: A Distinction Between Membrane and Soluble Proteins

Soluble proteins often contain multiple structural domains, which are shuffled or recombined to gain new functions in the course of evolution. We examined integral membrane proteins for evidence of this mechanism using a classification of polytopic transmembrane domains. Surprisingly, in contrast to the situation in aqueous solution, we found that recombination of structural domains is not common inside membranes: the majority of integral membrane proteins contain only a single polytopic membrane domain. We suggest that non-covalent oligomeric associations, which are common in membrane proteins, may provide an alternative source of evolutionary diversity in this class of proteins. Introduction Protein domains are often mixed to facilitate evolution, usually by recombination events that place them in single polypeptides (1-4). Proteomes from archae, prokarya, and eukarya were studied using a structure-based classification (SCOP) (5), and it was found that a large majority of domains (approximately 65% in prokarya and approximately 80% in eukarya) are combined with other domains (6). Thus, evolution appears to use recombination of domains to generate new protein structures and functions. However, the structural database is overwhelmingly biased in favor of soluble proteins, raising the question of whether the process of domain recombination is also used inside membranes. Using our classification of polytopic trans-membrane domains into ~650 families (7), we examined 26 proteomes, and found that mixed domain proteins are much less abundant inside membranes than in the aqueous regions of a