Amino acid substitutions at protein-protein interfaces that modulate the oligomeric state.

ABSTRACT

Despite similarities in their sequence and structure, there are a number of homologous proteins that adopt various oligomeric states. Comparisons of these homologous protein pairs, in terms of residue substitutions at the protein-protein interfaces, have provided fundamental characteristics that describe how proteins interact with each other. We have prepared a dataset composed of pairs of related proteins with different homo-oligomeric states. Using the protein complexes, the interface residues were identified, and using structural alignments, the shadow-interface residues have been defined as the surface residues that align with the interface residues. Subsequently, we investigated residue substitutions between the interfaces and the shadow interfaces. Based on the degree of the contributions to the interactions, the aligned sites of the interfaces and shadow interfaces were divided into primary and secondary sites; the primary sites are the focus of this work. The primary sites were further classified into two groups (i.e. exposed and buried) based on the degree to which the residue is buried within the shadow interfaces. Using these classifications, two simple mechanisms that mediate the oligomeric states were identified. In the primary-exposed sites, the residues on the shadow interfaces are replaced by more hydrophobic or aromatic residues, which are physicochemically favored at protein-protein interfaces. In the primary-buried sites, the residues on the shadow interfaces are replaced by larger residues that protrude into other proteins. These simple rules are satisfied in 23 out of 25 Structural Classification of Proteins (SCOP) families with a different-oligomeric-state pair, and thus represent a basic strategy for modulating protein associations and dissociations.