Pleckstrin homology domain (PH_domain)
Type: Domain

Pleckstrin homology (PH) domains are small modular domains that occur in a large variety of proteins and they have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner, enabling them to interact with other components of signal transduction pathways. They share little sequence conservation, but all have a common fold, which is electrostatically polarised. The domains can bind phosphatidylinositol within biological membranes and proteins such as the beta/gamma subunits of heterotrimeric G proteins and protein kinase C . PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to phosphoinositide phosphates (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-terminal of the domain, which are not conserved across all PH domains .

PH domains have been found to possess inserted domains (such as in PLC gamma, syntrophins) and to be inserted within other domains. Mutations in Brutons tyrosine kinase (Btk) within its PH domain cause X-linked agammaglobulinaemia (XLA) in patients. Point mutations cluster into the positively charged end of the molecule around the predicted binding site for phosphatidylinositol lipids.

The 3D structure of several PH domains has been determined . All known cases have a common structure consisting of two perpendicular anti-parallel β-sheets, followed by a C-terminal amphipathic helix. The loops connecting the β-strands differ greatly in length, making the PH domain relatively difficult to detect. There are no totally invariant residues within the PH domain.

Proteins reported to contain one more PH domains belong to the following families:

Pleckstrin, the protein where this domain was first detected, is the major substrate of protein kinase C in platelets. Pleckstrin is one of the rare proteins to contains two PH domains.

Ser/Thr protein kinases such as the Akt/Rac family, the beta-adrenergic receptor kinases, the mu isoform of PKC and the trypanosomal NrkA family.

Tyrosine protein kinases belonging to the Btk/Itk/Tec subfamily.

Insulin Receptor Substrate 1 (IRS-1).

Regulators of small G-proteins like guanine nucleotide releasing factor GNRP (Ras-GRF) (which contains 2 PH domains), guanine nucleotide exchange proteins like vav, dbl, SoS and Saccharomyces cerevisiae CDC24, GTPase activating proteins like rasGAP and BEM2/IPL2, and the human break point cluster protein bcr.

Cytoskeletal proteins such as dynamin (see

), Caenorhabditis elegans kinesin-like protein unc-104 (see

), spectrin beta-chain, syntrophin (2 PH domains) and S. cerevisiae nuclear migration protein NUM1.

Mammalian phosphatidylinositol-specific phospholipase C (PI-PLC) (see

) isoforms gamma and delta. Isoform gamma contains two PH domains, the second one is split into two parts separated by about 400 residues.

Oxysterol binding proteins OSBP, S. cerevisiae OSH1 and YHR073w.

Mouse protein citron, a putative rho/rac effector that binds to the GTP-bound forms of rho and rac.

Several S. cerevisiae proteins involved in cell cycle regulation and bud formation like BEM2, BEM3, BUD4 and the BEM1-binding proteins BOI2 (BEB1) and BOI1 (BOB1).

C. elegans protein MIG-10.

C. elegans hypothetical proteins C04D8.1, K06H7.4 and ZK632.12.

S. cerevisiae hypothetical proteins YBR129c and YHR155w.