6v4u
From Proteopedia
Cryo-EM structure of SMCR8-C9orf72-WDR41 complex
Structural highlights
FunctionWDR41_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).[1] [2] [3] [4] Publication Abstract from PubMedMutation of C9orf72 is the most prevalent defect associated with amyotrophic lateral sclerosis and frontotemporal degeneration(1). Together with hexanucleotide-repeat expansion(2,3), haploinsufficiency of C9orf72 contributes to neuronal dysfunction(4-6). Here we determine the structure of the C9orf72-SMCR8-WDR41 complex by cryo-electron microscopy. C9orf72 and SMCR8 both contain longin and DENN (differentially expressed in normal and neoplastic cells) domains(7), and WDR41 is a beta-propeller protein that binds to SMCR8 such that the whole structure resembles an eye slip hook. Contacts between WDR41 and the DENN domain of SMCR8 drive the lysosomal localization of the complex in conditions of amino acid starvation. The structure suggested that C9orf72-SMCR8 is a GTPase-activating protein (GAP), and we found that C9orf72-SMCR8-WDR41 acts as a GAP for the ARF family of small GTPases. These data shed light on the function of C9orf72 in normal physiology, and in amyotrophic lateral sclerosis and frontotemporal degeneration. Structure of the C9orf72 ARF GAP complex that is haploinsufficient in ALS and FTD.,Su MY, Fromm SA, Zoncu R, Hurley JH Nature. 2020 Aug 26. pii: 10.1038/s41586-020-2633-x. doi:, 10.1038/s41586-020-2633-x. PMID:32848248[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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