7mge

From Proteopedia

Structure of C9orf72:SMCR8:WDR41 in complex with ARF1

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:	, ,
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).^[1] ^[2] ^[3] ^[4]

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^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Sellier C, Campanari ML, Julie Corbier C, Gaucherot A, Kolb-Cheynel I, Oulad-Abdelghani M, Ruffenach F, Page A, Ciura S, Kabashi E, Charlet-Berguerand N. Loss of C9ORF72 impairs autophagy and synergizes with polyQ Ataxin-2 to induce motor neuron dysfunction and cell death. EMBO J. 2016 Jun 15;35(12):1276-97. doi: 10.15252/embj.201593350. Epub 2016 Apr, 21. PMID:27103069 doi:http://dx.doi.org/10.15252/embj.201593350
↑ Sullivan PM, Zhou X, Robins AM, Paushter DH, Kim D, Smolka MB, Hu F. The ALS/FTLD associated protein C9orf72 associates with SMCR8 and WDR41 to regulate the autophagy-lysosome pathway. Acta Neuropathol Commun. 2016 May 18;4(1):51. doi: 10.1186/s40478-016-0324-5. PMID:27193190 doi:http://dx.doi.org/10.1186/s40478-016-0324-5
↑ Yang M, Liang C, Swaminathan K, Herrlinger S, Lai F, Shiekhattar R, Chen JF. A C9ORF72/SMCR8-containing complex regulates ULK1 and plays a dual role in autophagy. Sci Adv. 2016 Sep 2;2(9):e1601167. doi: 10.1126/sciadv.1601167. eCollection 2016 , Sep. PMID:27617292 doi:http://dx.doi.org/10.1126/sciadv.1601167
↑ Jung J, Nayak A, Schaeffer V, Starzetz T, Kirsch AK, Muller S, Dikic I, Mittelbronn M, Behrends C. Multiplex image-based autophagy RNAi screening identifies SMCR8 as ULK1 kinase activity and gene expression regulator. Elife. 2017 Feb 14;6. doi: 10.7554/eLife.23063. PMID:28195531 doi:http://dx.doi.org/10.7554/eLife.23063
↑ Su MY, Fromm SA, Remis J, Toso DB, Hurley JH. Structural basis for the ARF GAP activity and specificity of the C9orf72 complex. Nat Commun. 2021 Jun 18;12(1):3786. PMID:34145292 doi:10.1038/s41467-021-24081-0