InterPro domain: IPR012466

This PH-like domain can be found in the N-terminal region of NECAPs (also known as adaptin ear-binding coat-associated proteins). NECAPs are alpha-ear-binding proteins that enrich on clathrin-coated vesicles (CCVs). NECAP-1 is expressed in brain and non-neuronal tissues and cells while NECAP-2 is ubiquitously expressed. The PH-like domain of NECAPs is a protein-binding interface that mimics the FxDxF motif binding properties of the alpha-ear and is called PHear (PH fold with ear-like function) domain [ 1 ].

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 [ 2 , 3 , 4 , 5 , 6 ].

1. The NECAP PHear domain increases clathrin accessory protein binding potential. EMBO J. 26, 4066-77
2. Pleckstrin homology (PH) like domains - versatile modules in protein-protein interaction platforms. FEBS Lett. 586, 2662-73
3. Pleckstrin homology (PH) domains and phosphoinositides. Biochem. Soc. Symp. 120, 81-93
4. Pleckstrin homology domains: two halves make a hole? Cell 32, 574-6
5. Membrane targeting by pleckstrin homology domains. Curr. Top. Microbiol. Immunol. 282, 49-88
6. Pleckstrin homology domains: not just for phosphoinositides. Biochem. Soc. Trans. , 707-11