HIKE, a candidate protein binding site for PH domains, is a major regulatory region of G? proteins

HIKE is a highly conserved sequence motif that selectively occurs in proteins candidate to bind PH domains, e.g., the β subunit of heterotrimeric G proteins, kinases, ankyrin and kinesin. Thus, the HIKE region has been predicted to be a protein docking site for PH domains. This work evidentiates recent experimental evidence that unambiguously defines the functional role of HIKE in Gβ as a multiple effector docking site and as a major regulatory region of G protein's function. Indeed, the Gβ HIKE interacts with the β-adrenergic receptor kinase, Gα, Gγ, adenylyl cyclase 2, phospholipase C β2, inward rectifier K channels, calcium channel α1B, calmodulin, phosducin, ste20. Quite interestingly, HIKE is located in the Gβ region that faces the cell membrane. Thus, HIKE also interacts with the cell membrane and may dynamically regulate membrane vs effector binding of the Gαβγ trimer. These findings fulfill a major prediction of the HIKE model, i.e., that HIKE is a regulatory region for protein-protein interactions. A role of HIKE as a proteic binding site for PH domains is supported by the profound influence of HIKE mutations on the largely PH-mediated binding of β-ARK to Gβ. Proteins 1999;35:360–363.