Related Protein–Protein Interaction Modules Present Drastically Different Surface Topographies Despite A Conserved Helical Platform

Abstract

The subcellular localization of cAMP-dependent protein kinase (PKA) occurs through interaction with A-Kinase Anchoring Proteins (AKAPs). AKAPs bind to the PKA regulatory subunit dimer of both type Iα and type IIα (RIα and RIIα). RIα and RIIα display characteristic localization within different cell types, which is maintained by interaction of AKAPs with the N-terminal dimerization and docking domain (D/D) of the respective regulatory subunit. Previously, we reported the solution structure of RIIa D/D module, both free and bound to AKAPs. We have now solved the solution structure of the dimerization and docking domain of the type Iα regulatory dimer subunit (RIα D/D). RIα D/D is a compact docking module, with unusual interchain disulfide bonds that help maintain the AKAP interaction surface. In contrast to the shallow hydrophobic groove for AKAP binding across the surface of the RIIα D/D dimeric interface, the RIα D/D module presents a deep cleft for proposed AKAP binding. RIα and RIIα D/D interaction modules present drastically differing dimeric topographies, despite a conserved X-type four-helix bundle structure.