Interrogating protein interaction networks through structural biology

Protein–protein interactions are central to most biological processes. Although much recent effort has been put into methods to identify interacting partners, there has been a limited focus on how these interactions compare with those known from three-dimensional (3D) structures. Because comparison of protein interactions often involves considering homologous, but not identical, proteins, a key issue is whether proteins that are homologous to an interacting pair will interact in the same way, or interact at all. Accordingly, we describe a method to test putative interactions on complexes of known 3D structure. Given a 3D complex and alignments of homologues of the interacting proteins, we assess the fit of any possible interacting pair on the complex by using empirical potentials. For studies of interacting protein families that show different specificities, the method provides a ranking of interacting pairs useful for prioritizing experiments. We evaluate the method on interacting families of proteins with multiple complex structures. We then consider the fibroblast growth factor/receptor system and explore the intersection between complexes of known structure and interactions proposed between yeast proteins by methods such as two-hybrids. We provide confirmation for several interactions, in addition to suggesting molecular details of how they occur.