PH domain leucine-rich repeat protein phosphatase family Pleckstrin homology-like domain
The PHLPP family has members PHLPP1 (also called hSCOP/Suprachiasmatic nucleus circadian oscillatory protein; PLEKHE1/Pleckstrin homology domain-containing family E member 1) and PHLPP2 (PHLPP-like/PHLPPL). The PHLPP family of novel Ser/Thr phosphatases serve as important regulators of cell survival and apoptosis. PHLPP isozymes catalyze the dephosphorylation of a conserved regulatory motif, the hydrophobic motif, on the AGC kinases Akt, PKC, and S6 kinase, as well as an inhibitory site on the kinase Mst1, to inhibit cellular proliferation and induce apoptosis and negatively regulates ERK1/2 activation. Reductions in their expression have been detected in several cancers and linked to cancer progression. PHLPP1 and PHLPP2 both contain an N-terminal PH domain, followed by 21 LRR (leucine-rich) repeats, and a C-terminal PP2C-like domain. 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.
Jiyao W et al.(2023). "The conserved domain database in 2023.",