InterPro domain: IPR043453

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 [ 1 ]. 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 [ 2 ]. 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 [ 3 ]. 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 [ 4 ].

Slm1 is a component of the target of rapamycin complex 2 (TORC2) signaling pathway. It plays a role in the regulation of actin organization and is a target of sphingolipid signaling during the heat shock response [ 4 ]. Slm1 contains a single PH domain that binds PtdIns(4,5)P2, PtdIns(4)P, and dihydrosphingosine 1-phosphate (DHS-1P). Slm1 possesses two binding sites for anionic lipids. The non-canonical binding site of the PH domain of Slm1 is used for ligand binding, and it is proposed that beta-spectrin, Tiam1 and ArhGAP9 also have this type of phosphoinositide binding site [ 5 ].

1. Pleckstrin homology (PH) like domains - versatile modules in protein-protein interaction platforms. FEBS Lett. 586, 2662-73
2. Pleckstrin homology domains: not just for phosphoinositides. Biochem. Soc. Trans. 32, 707-11
3. Membrane targeting by pleckstrin homology domains. Curr. Top. Microbiol. Immunol. 282, 49-88
4. A systematic screen for protein-lipid interactions in Saccharomyces cerevisiae. Mol. Syst. Biol. 6, 430
5. Structural Analyses of the Slm1-PH Domain Demonstrate Ligand Binding in the Non-Canonical Site. PLoS ONE 7, e36526