7r03
From Proteopedia
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==Neurofibromin occluded conformation== | ==Neurofibromin occluded conformation== | ||
| - | <StructureSection load='7r03' size='340' side='right'caption='[[7r03]]' scene=''> | + | <StructureSection load='7r03' size='340' side='right'caption='[[7r03]], [[Resolution|resolution]] 3.60Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7R03 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7R03 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7r03]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7R03 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7R03 FirstGlance]. <br> |
| - | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7r03 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7r03 OCA], [https://pdbe.org/7r03 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7r03 RCSB], [https://www.ebi.ac.uk/pdbsum/7r03 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7r03 ProSAT]</span></td></tr> | + | </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[7r04|7r04]]</div></td></tr> |
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7r03 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7r03 OCA], [https://pdbe.org/7r03 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7r03 RCSB], [https://www.ebi.ac.uk/pdbsum/7r03 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7r03 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Disease == | ||
| + | [[https://www.uniprot.org/uniprot/NF1_HUMAN NF1_HUMAN]] Defects in NF1 are the cause of neurofibromatosis type 1 (NF1) [MIM:[https://omim.org/entry/162200 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.<ref>PMID:2114220</ref> <ref>PMID:1302608</ref> <ref>PMID:7981679</ref> <ref>PMID:8081387</ref> <ref>PMID:8544190</ref> <ref>PMID:8834249</ref> <ref>PMID:8807336</ref> <ref>PMID:9003501</ref> <ref>PMID:9150739</ref> <ref>PMID:9101300</ref> <ref>PMID:9298829</ref> <ref>PMID:9668168</ref> <ref>PMID:10336779</ref> <ref>PMID:11258625</ref> <ref>PMID:10220149</ref> <ref>PMID:10712197</ref> <ref>PMID:10607834</ref> <ref>PMID:10980545</ref> <ref>PMID:11735023</ref> <ref>PMID:11857752</ref> <ref>PMID:12522551</ref> <ref>PMID:12552569</ref> <ref>PMID:12746402</ref> <ref>PMID:15523642</ref> <ref>PMID:15146469</ref> <ref>PMID:15060124</ref> <ref>PMID:15520408</ref> <ref>PMID:15948193</ref> <ref>PMID:21838856</ref> Defects in NF1 are a cause of juvenile myelomonocytic leukemia (JMML) [MIM:[https://omim.org/entry/607785 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:[https://omim.org/entry/193520 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:[https://omim.org/entry/162210 162210]]. Familial spinal NF is considered to be an alternative form of neurofibromatosis, showing multiple spinal tumors.<ref>PMID:11704931</ref> Defects in NF1 are a cause of neurofibromatosis-Noonan syndrome (NFNS) [MIM:[https://omim.org/entry/601321 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.<ref>PMID:12707950</ref> <ref>PMID:16380919</ref> <ref>PMID:19845691</ref> Defects in NF1 may be a cause of colorectal cancer (CRC) [MIM:[https://omim.org/entry/114500 114500]]. | ||
| + | == Function == | ||
| + | [[https://www.uniprot.org/uniprot/NF1_HUMAN 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.<ref>PMID:2121371</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == 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<ref>PMID:35353986</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7r03" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Chaker-Margot M]] | + | [[Category: Chaker-Margot, M]] |
| - | [[Category: Maier T]] | + | [[Category: Maier, T]] |
| - | [[Category: Scheffzek K]] | + | [[Category: Scheffzek, K]] |
| + | [[Category: Gap]] | ||
| + | [[Category: Homodimer]] | ||
| + | [[Category: Neurofibromatosis type i]] | ||
| + | [[Category: Signaling protein]] | ||
| + | [[Category: Signalling protein]] | ||
Revision as of 10:21, 13 April 2022
Neurofibromin occluded conformation
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