https://en.wikipedia.org/wiki/Neurofibromin_1
Neurofibromin 1 (NF1) is a gene in humans that is located on chromosome 17.[5] NF1 codes for neurofibromin, a GTPase-activating protein that negatively regulates RAS/MAPK pathway activity[5] by accelerating the hydrolysis of Ras-bound GTP.[6][7] There are currently five known neurofibromin isoforms that are expressed in different tissues and perform different functions.[8] NF1 has a high mutation rate and mutations in NF1 can alter cellular growth control, and neural development, resulting in neurofibromatosis type 1 (NF1, also known as von Recklinghausen syndrome).[5] Symptoms of NF1 include cutaneous neurofibromas, café au lait pigment spots, plexiform neurofibromas, skeletal defects and optic nerve gliomas.[9][5]
Gene
NF1 encodes the protein neurofibromin, a GTPase-activating protein, which primarily regulates the protein Ras.[6] NF1 is located on the long arm of chromosome 17, position q11.2[5] and was identified in 1990 through positional cloning.[6] NF1 spans over 350-kb of genomic DNA and contains 62 exons.[8] 58 of these exons are constitutive and 4 exhibit alternative splicing ( 9a, 10a-2, 23a, and 28a).[8] The genomic sequence starts 4,951-bp upstream of the transcription start site and 5,334-bp upstream of the translation initiation codon, with the length of the 5’ UTR being 484-bp long.[10]
There are three genes that are present within intron 27b of NF1. These genes are EVI2B, EVI2A and OMG, which are encoded on the opposite strand and are transcribed in the opposite direction of NF1.[10] EVI2A and EVI2B are human homologs of the Evi-2A and Evi-2B genes in mice that encode proteins related to leukemia in mice.[6] OMG is a membrane glycoprotein that is expressed in the human central nervous system during myelination of nerve cells.[10]
Function
Through its NF1-GRD domain, neurofibromin increases the rate of GTP hydrolysis of Ras, and acts as a tumor suppressor by reducing Ras activity.[8] When the Ras-Nf1 complex assembles, active Ras binds in a groove that is present in the neurofibromin catalytic domain.[8] This binding occurs through Ras switch regions I and II, and an arginine finger present in neurofibromin.[8] The interaction between Ras and neurofibromin causes GAP-stimulated hydrolysis of GTP to GDP.[8] This process depends on the stabilization of residues in the Ras switch I and switch II regions, which drives Ras into the confirmation required for enzymatic function.[8] This interaction between Ras and neurofibromin also requires the transition state of GDP hydrolysis to be stabilized, which is performed through the insertion of the positively charged arginine finger into the Ras active site.[8] This neutralizes the negative charges that are present on GTP during phosphoryl transfer.[8] By hydrolyzing GTP to GDP, neurofibromin inactivates Ras and therefore negatively regulates the Ras pathway, which controls the expression of genes involved in apoptosis, the cell cycle, cell differentiation or migration.[8]Neurofibromin is also known to interact with CASK through syndecan, a protein which is involved in the KIF17/ABPA1/CASK/LIN7A complex, which is involved in trafficking GRIN2B to the synapse. This suggests that neurofibromin* has a role in the transportation of the NMDA receptor subunits to the synapse and its membrane. Neurofibromin* is also believed to be involved in the synaptic ATP-PKA-cAMP pathway, through modulation of adenylyl cyclase. It is also known to bind the caveolin 1, a protein which regulates p21ras, PKC and growth response factors.[8]
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