Interaction interfaces of protein domains are not topologically equivalent across families within superfamilies: Implications for metabolic and signaling pathways

Abstract

Using a data set of aligned protein domain superfamilies of known three-dimensional structure, we compared the location of interdomain interfaces on the tertiary folds between members of distantly related protein domain superfamilies. The data set analyzed is comprised of interdomain interfaces, with domains occurring within a polypeptide chain and those between two polypeptide chains. We observe that, in general, the interfaces between protein domains are formed entirely in different locations on the tertiary folds in such pairs. This variation in the location of interface happens in protein domains involved in a wide range of functions, such as enzymes, adapters, and domains that bind protein ligands, or cofactors. While basic biochemical functionality is preserved at the domain superfamily level, the effect of biochemical function on protein assemblies is different in these protein domains related by superfamily. The divergence between proteins, in most cases, is coupled with domain recruitment, with different modes of interaction with the recruited domain. This is in complete contrast to the observation that in closely related homologous protein domains, almost always the interaction interfaces are topologically equivalent. In a small subset of interacting domains within proteins related by remote homology, we observe that the relative positioning of domains with respect to one another is preserved. Based on the analysis of multidomain proteins of known or unknown structure, we suggest that variation in protein-protein interactions in members within a superfamily could serve as diverging points in otherwise parallel metabolic or signaling pathways. We discuss a few representative cases of diverging pathways involving domains in a superfamily. Proteins 2005;58:339 -353.

Variation in structural location and amino acid conservation of functional sites in protein domain families

“…However, functional sites can vary in subfamilies and homologous protein sequences can perform different functions using a different set of functional residues. Accordingly, interaction interfaces can vary in their location in distant homologues and this has to be considered if interaction interfaces are inferred from homologous proteins [15,16]. …”

PRODOC: a resource for the comparison of tethered protein domain architectures with in-built information on remotely related domain families

“…We have formed a dataset of distantly related Pfam domain families by relating Pfam families with proteins of known three-dimensional structure and by identifying new potential sequence superfamilies (29,30). This information is used in the domain architecture search tool to result in the identification of distantly related multi-domain proteins with one or more domains related by a superfamily connection (14). …”

“…Knowledge of the functions of the individual domains of a multi-domain protein contributes to our understanding of the properties of the protein as a whole (4–6). Viewing multi-domain proteins as sequences of domains also enables the identification of gene fusion events, interacting proteins (7,8) and preferred domain associations (9–14), and the comparison of sequences of domains helps in obtaining clues about domain function. For example, in two multi-domain proteins with many common domains, alignment of a region of unknown function with a domain of known function raises the possibility of a distant relationship between the region of unknown function and the aligned domain.…”

“…Such searches enable the user to study the evolution of the functions of multi-domain proteins. It has been suggested that homologous protein domains with extensive sequence divergence, forming protein domain superfamilies, are involved in novel domain combinations during gene fusion events while retaining the broad nature of the function (14). It is suggested that such variations in domain recruitment and high sequence divergence form turning points in otherwise similar biochemical pathways (14).…”

Accommodation of profound sequence differences at the interfaces of eubacterial RNA polymerase multi-protein assembly

“…Study of interface conservation in proteins related at level of family/superfamily shows that as sequence divergence becomes extensive (as in protein domains related by superfamily), proteins tend to change their partners [9]. RNA polymerase subunits, although some of them show extensive divergence, seem to interact with the same partners.…”