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Neurofibromin-1 Pleckstrin homology-like domain Neurofibromin (NF1) contains a N-terminal RasGAP domain, followed by a Sec14-like domain, and a PH domain. Surprisingly, in neurofibromin the PH domain alone is not sufficient for phospholipid binding and instead requires the presence of the Sec-14 domain. The Sec-14 domain has been shown to bind 1-(3-sn-phosphatidyl)-sn-glycerol (PtdGro), (3-sn-phosphatidyl)-ethanolamine (PtdEtn) and -choline (PtdCho) and to a minor extent to (3-sn-phosphatidyl)-l-serine (PtdSer) and 1-(3-sn-phosphatidyl)-d-myo-inositol (PtdIns). Neurofibromatosis type 1 (also known as von Recklinghausen neurofibromatosis or NF1) is a genetic disorder caused by alterations in the tumor suppressor gene NF1. Hallmark symptoms include neural crest derived tumors, pigmentation anomalies, bone deformations, and learning disabilities. Mutations of the tumour suppressor gene NF1 are responsible for disease pathogenesis, with 90% of the alterations being nonsense codons. 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.",