2e2x

Sec14 Homology Module of Neurofibromin in complex with phosphatitylethanolamine

spinqualitylabelsall models 2e2x, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2e2x is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: PEV, POP Related: 2d4q Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [NF1_HUMAN] Defects in NF1 are the cause of neurofibromatosis type 1 (NF1) [MIM:162200]; also known as von Recklinghausen syndrome. A disease characterized by patches of skin pigmentation (cafe-au-lait spots), Lisch nodules of the iris, tumors in the peripheral nervous system and fibromatous skin tumors. Individuals with the disorder have increased susceptibility to the development of benign and malignant tumors. Defects in NF1 are a cause of juvenile myelomonocytic leukemia (JMML) [MIM:607785]. JMML is a pediatric myelodysplastic syndrome that constitutes approximately 30% of childhood cases of myelodysplastic syndrome (MDS) and 2% of leukemia. Germline mutations of NF1 account for the association of JMML with type 1 neurofibromatosis (NF1). Defects in NF1 are the cause of Watson syndrome (WS) [MIM:193520]. WS is characterized by the presence of pulmonary stenosis, cafe-au-lait spots, and mental retardation. WS is considered as an atypical form of NF1. Defects in NF1 are a cause of familial spinal neurofibromatosis (FSNF) [MIM:162210]. Familial spinal NF is considered to be an alternative form of neurofibromatosis, showing multiple spinal tumors. Defects in NF1 are a cause of neurofibromatosis-Noonan syndrome (NFNS) [MIM:601321]. NFNS is characterized by manifestations of both NF1 and Noonan syndrome (NS). NS is a disorder characterized by dysmorphic facial features, short stature, hypertelorism, cardiac anomalies, deafness, motor delay, and a bleeding diathesis. Defects in NF1 may be a cause of colorectal cancer (CRC) [MIM:114500]. Function [NF1_HUMAN] Stimulates the GTPase activity of Ras. NF1 shows greater affinity for Ras GAP, but lower specific activity. May be a regulator of Ras activity. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed Neurofibromin is the protein product of the tumor suppressor gene NF1, alterations of which are responsible for the pathogenesis of the common disorder Neurofibromatosis type I (NF1). The only well-characterized function of neurofibromin is its RasGAP activity, contained in the central GAP related domain (GRD). By solving the crystal structure of a 31 kDa fragment at the C-terminal end of the GRD we have recently identified a novel bipartite lipid-binding module composed of a Sec14 homologous and a previously undetected pleckstrin homology (PH)-like domain. Using lipid exchange assays along with mass spectrometry we show here that the Sec14-like portion binds to 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). Phosphorylated PtdIns (PtdInsPs) are not detected as binders in the mass spectrometry assay, but their soluble inositol-phosphate headgroups and related compounds can inhibit the lipid exchange reaction. We also present here the crystal structure of this module with the Sec14 portion bound to a cellular glycerophospholipid ligand. Our structure has model character for the substrate-bound form of yeast Sec14p, of which only detergent bound structures are available so far. To assess potential regulation of the lipid exchange reaction in detail, we present a novel strategy using nanospray mass spectrometry. Ion intensities of initial phospholipids and exchanged deuterated analogues bound by the protein module allow the quantitative analysis of differences in the exchange activity under various conditions. The sec14 homology module of neurofibromin binds cellular glycerophospholipids: mass spectrometry and structure of a lipid complex.,Welti S, Fraterman S, D'Angelo I, Wilm M, Scheffzek K J Mol Biol. 2007 Feb 16;366(2):551-62. Epub 2006 Nov 18. PMID:17187824 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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