Primate cytomegalovirus US12 gene family: a distinct and diverse clade of seven-transmembrane proteins.

Human cytomegalovirus (HCMV; Human herpesvirus 5) and the other betaherpesviruses encode a number of distinct gene families, including the US12 family, which is represented only in the cytomegaloviruses of higher primates, and is comprised of a set of 10 contiguous genes (US12 through US21), each encoding a seven-transmembrane (7TM) protein. Nonessential for replication in cell culture but well-conserved among clinical isolates, little is known of possible US12 family member functions, other than a previously identified amino acid sequence similarity between US21 and a group of 7TM proteins that include known inhibitors of apoptosis, and a very limited description of similarity between US12 family members and G-protein-coupled receptors (GPCR). As a prelude to biochemical analysis, we have conducted a detailed analysis of the relationships among US12 family members and between these proteins and other proteins, particularly GPCR and other 7TM molecules. In most cases, the closest relatives of individual genes are their colinear counterparts in the other viruses. Thus, the initial duplication and divergence events that resulted in the current version of the US12 family preceded divergence of the rhesus and hominoid lineages. Our phylogenetic analysis indicates that the US12 family represents a distinct branch of the 7TM superfamily. Although they are distantly related, at least some of the US12 family members may have GPCR-related properties, but they are also likely to embody functions and mechanisms that differ from more conventional GPCRs. Our analyses suggest that the 7TM structure of US12 family members constitutes a functionally flexible structural scaffold that can be readily adapted to diverse functional ends. This strategy may be the driving force in the emergence of the several families of duplicated and diverged betaherpesvirus genes.