8e20

Cryo-EM structure of the full-length human NF1 dimer

spinqualitylabelsall models 8e20, resolution 3.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8e20 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.6Å 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 The majority of pathogenic mutations in the neurofibromatosis type I (NF1) gene reduce total neurofibromin protein expression through premature truncation or microdeletion, but it is less well understood how loss-of-function missense variants drive NF1 disease. We have found that patient variants in codons 844 to 848, which correlate with a severe phenotype, cause protein instability and exert an additional dominant-negative action whereby wild-type neurofibromin also becomes destabilized through protein dimerization. We have used our neurofibromin cryogenic electron microscopy structure to predict and validate other patient variants that act through a similar mechanism. This provides a foundation for understanding genotype-phenotype correlations and has important implications for patient counseling, disease management, and therapeutics. Destabilizing NF1 variants act in a dominant negative manner through neurofibromin dimerization.,Young LC, Goldstein de Salazar R, Han SW, Huang ZYS, Merk A, Drew M, Darling J, Wall V, Grisshammer R, Cheng A, Allison MR, Sale MJ, Nissley DV, Esposito D, Ognjenovic J, McCormick F Proc Natl Acad Sci U S A. 2023 Jan 31;120(5):e2208960120. doi: , 10.1073/pnas.2208960120. Epub 2023 Jan 23. PMID:36689660 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Neurofibromin

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