Pleckstrin Homology (PH) domains are ~100 amino acid segments found in a wide variety of proteins which have roles in cellular signal transduction. Many of these proteins, when mutated result in human developmental disorders and cancer. Many proteins with important enzymatic and/or signaling roles have PH domains. All phospholipase C enzymes have at least one PH domain. Most regulators of small G proteins such as Ras and Rac/Rho contain PH domains. Many important protein kinases, such as protein kinase B (a.k.a. Akt), Bruton's tyrosine kinase (Btk) and the beta-adrenergic kinase 1 and 2 contain PH domains. PH domains seem to function in localizing proteins to cellular membranes and allowing protein complexes to form in a signal dependent manner. Some of them do this primarily by binding directly to membrane lipids, in some cases with quite high specificity. One important group of these molecules bind, through their PH domains, to 3-phosphorylated inositol lipids, which are rapidly generated in membranes by activation of PI-3 kinase enzymes. PI-3 kinases are in turn activated by growth factors and chemotactic signals, and so this pathway is responsible for growth factor effects, chemotaxis and many other phenomena. Other PH domains have less specific membrane binding but apparently make up for this by binding other proteins. So PH domains, along with Src-homology 2 and 3 domains and many other kinds of signalling domain are of fundamental biological significance. Diagrams of proteins containing PH domains are shown below. This diagrams were published in a review I wrote for BioEssays a few years ago Medline Link. I also wrote a more recent review for the Encyclopedia of Molecular Biology, which describes how PH domains are structurally related to the phosphotyrosine binding (Ptb) domains of proteins such as Shc and IRS-1. This finding was a complete surprise since no-one working on these domains suspected this based on the amino acid sequence which appears to be totally unrelated. More recently still the Enabled-Vasp homology domain 1 (EVH1) was also shown to belong structurally to this large family of binding modules. In fact, PH domains and their relatives are the most abundant type of sigalling domain found in sequenced genomes.
Above are diagrams of some of the numerous proteins which have PH domains, taken from my BioEssays review. Typically these molecules have many other kinds of binding domain such as SH2 domains (SH2), SH3 domains (3), PtB domains (Ptb), proline rich regions (P), C2 domains (C), tyrosine phosphorylation sites (Y) and others. Such proteins also often contain enzymatic domains such as serine/threonine kinases (S/T kinase), tyrosine kinase (Y kinase), phospholipase C (Plc A and B), GAP and GEFs for ras family small G proteins (ras-GEF, ras-GAP) and Dbl-homology domains which are GEFs for rac-rho family small G proteins (DH). The PH domains are presumably involved in regulating the binding partners, subcellular location and hence activity of these proteins. Return to previous