6ulg
From Proteopedia
Cryo-EM structure of the FLCN-FNIP2-Rag-Ragulator complex
Structural highlights
DiseaseFLCN_HUMAN Familial spontaneous pneumothorax;Birt-Hogg-Dube syndrome. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The gene represented in this entry may be involved in disease pathogenesis. FunctionFLCN_HUMAN May play a role in the pathogenesis of an uncommon form of kidney cancer through its association with an inherited disorder of the hair follicle (fibrofolliculomas). May be a tumor suppressor. May be involved in colorectal tumorigenesis. May be involved in energy and/or nutrient sensing through the AMPK and mTOR signaling pathways. May regulate phosphorylation of RPS6KB1.[1] [2] [3] Publication Abstract from PubMedmTORC1 controls anabolic and catabolic processes in response to nutrients through the Rag GTPase heterodimer, which is regulated by multiple upstream protein complexes. One such regulator, FLCN-FNIP2, is a GTPase activating protein (GAP) for RagC/D, but despite its important role, how it activates the Rag GTPase heterodimer remains unknown. We used cryo-EM to determine the structure of FLCN-FNIP2 in a complex with the Rag GTPases and Ragulator. FLCN-FNIP2 adopts an extended conformation with two pairs of heterodimerized domains. The Longin domains heterodimerize and contact both nucleotide binding domains of the Rag heterodimer, while the DENN domains interact at the distal end of the structure. Biochemical analyses reveal a conserved arginine on FLCN as the catalytic arginine finger and lead us to interpret our structure as an on-pathway intermediate. These data reveal features of a GAP-GTPase interaction and the structure of a critical component of the nutrient-sensing mTORC1 pathway. Cryo-EM Structure of the Human FLCN-FNIP2-Rag-Ragulator Complex.,Shen K, Rogala KB, Chou HT, Huang RK, Yu Z, Sabatini DM Cell. 2019 Nov 5. pii: S0092-8674(19)31213-9. doi: 10.1016/j.cell.2019.10.036. PMID:31704029[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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