G Protein-Coupled Receptor Kinase 2 subgroup pleckstrin homology (PH) domain
GRKs are a family of serine-threonine kinases which phosphorylates activated G-protein coupled receptors leading to the release of the previously bound heterotrimeric G protein agonist and thus signal termination. There are seven mammalian GRKs (GRK1-7) grouped into three subfamilies: GRK1 (GRK1 and 7), GRK2 (GRK2 and 3), and GRK4 (GRK4-6). GRKs have three functional components: an N-terminal Regulators of G-protein signaling (RGS) which interacts with the seven-trans-membrane helical receptor protein and/or other membrane targets, a central catalytic protein kinase C (PKc) domain, and a C-terminal section containing a autophosphorylation region and a variable region that mediates membrane association. In both GRK2 (also known as beta-adrenergic receptor kinase-1) and GRK3 (beta-adrenergic receptor kinase-2), the C-terminal variable region contains a PH domain which gives binding specificity to Gbetagamma proteins. The GRK2 PH domain has an extended C-terminal helix, which mediates interactions with G beta gamma subunits. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.
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