7mge

Structure of C9orf72:SMCR8:WDR41 in complex with ARF1

spinqualitylabelsall models 7mge, resolution 3.94Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7mge is a 4 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 3.94Å Ligands: BEF, GDP, MG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function WDR41_HUMAN Non-catalytic component of the C9orf72-SMCR8 complex, a complex that has guanine nucleotide exchange factor (GEF) activity and regulates autophagy (PubMed:27193190, PubMed:27103069, PubMed:27617292, PubMed:28195531). The C9orf72-SMCR8 complex promotes the exchange of GDP to GTP, converting inactive GDP-bound RAB8A and RAB39B into their active GTP-bound form, thereby promoting autophagosome maturation (PubMed:27103069). The C9orf72-SMCR8 complex also acts as a negative regulator of autophagy initiation by interacting with the ATG1/ULK1 kinase complex and inhibiting its protein kinase activity (PubMed:27103069, PubMed:27617292). Publication Abstract from PubMed Mutation of C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontal temporal degeneration (FTD), which is attributed to both a gain and loss of function. C9orf72 forms a complex with SMCR8 and WDR41, which was reported to have GTPase activating protein activity toward ARF proteins, RAB8A, and RAB11A. We determined the cryo-EM structure of ARF1-GDP-BeF(3)(-) bound to C9orf72:SMCR8:WDR41. The SMCR8(longin) and C9orf72(longin) domains form the binding pocket for ARF1. One face of the C9orf72(longin) domain holds ARF1 in place, while the SMCR8(longin) positions the catalytic finger Arg147 in the ARF1 active site. Mutations in interfacial residues of ARF1 and C9orf72 reduced or eliminated GAP activity. RAB8A GAP required ~10-fold higher concentrations of the C9orf72 complex than for ARF1. These data support a specific function for the C9orf72 complex as an ARF GAP. The structure also provides a model for the active forms of the longin domain GAPs of FLCN and NPRL2 that regulate the Rag GTPases of the mTORC1 pathway. Structural basis for the ARF GAP activity and specificity of the C9orf72 complex.,Su MY, Fromm SA, Remis J, Toso DB, Hurley JH Nat Commun. 2021 Jun 18;12(1):3786. doi: 10.1038/s41467-021-24081-0. PMID:34145292 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also WD-repeat protein 3D structures

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