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oculocerebrorenal syndrome of Lowe 1 Pleckstrin homology-like domain OCRL1 (also called INPP5F, LOCR, NPHL2, or phosphatidylinositol polyphosphate 5-phosphatase) hydrolyzes phosphatidylinositol 4,5-bisphosphate (PtIns(4,5)P2) and the signaling molecule phosphatidylinositol 1,4,5-trisphosphate (PtIns(1,4,5)P3), and thereby modulates cellular signaling events. It interact with APPL1, FAM109A and FAM109B and several Rab GTPases which might both target them to the specific membranes and as well as stimulating the phosphatase activity. OCRL1 contains a PH domain and a Rho-GAP domain. Patients with Lowe syndrome suffer primarily from congenital cataracts, neonatal hypotonia, intellectual disability and Fanconi syndrome. Mutations in OCRL are also found in a subset of patients with type 2 Dent disease, who selectively suffer from renal proximal tubular dysfunction. 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.",