7r04 | pdb_00007r04

Neurofibromin in open conformation

spinqualitylabelsall models 7r04, resolution 3.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7r04 is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: GSP Related: 7r03 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. Publication Abstract from PubMed Mutations in the NF1 gene cause the familial genetic disease neurofibromatosis type I, as well as predisposition to cancer. The NF1 gene product, neurofibromin, is a GTPase-activating protein and acts as a tumor suppressor by negatively regulating the small GTPase, Ras. However, structural insights into neurofibromin activation remain incompletely defined. Here, we provide cryoelectron microscopy (cryo-EM) structures that reveal an extended neurofibromin homodimer in two functional states: an auto-inhibited state with occluded Ras-binding site and an asymmetric open state with an exposed Ras-binding site. Mechanistically, the transition to the active conformation is stimulated by nucleotide binding, which releases a lock that tethers the catalytic domain to an extended helical repeat scaffold in the occluded state. Structure-guided mutational analysis supports functional relevance of allosteric control. Disease-causing mutations are mapped and primarily impact neurofibromin stability. Our findings suggest a role for nucleotides in neurofibromin regulation and may lead to therapeutic modulation of Ras signaling. Structural basis of activation of the tumor suppressor protein neurofibromin.,Chaker-Margot M, Werten S, Dunzendorfer-Matt T, Lechner S, Ruepp A, Scheffzek K, Maier T Mol Cell. 2022 Apr 7;82(7):1288-1296.e5. doi: 10.1016/j.molcel.2022.03.011. Epub , 2022 Mar 29. PMID:35353986 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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