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| Title | Structural basis for the ARF GAP activity and specificity of the C9orf72 complex. |
|---|---|
| Journal, issue, pages | Nat Commun, Vol. 12, Issue 1, Page 3786, Year 2021 |
| Publish date | Jun 18, 2021 |
 Authors | Ming-Yuan Su / Simon A Fromm / Jonathan Remis / Daniel B Toso / James H Hurley /    |
| PubMed Abstract | 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 ...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 bound to C9orf72:SMCR8:WDR41. The SMCR8 and C9orf72 domains form the binding pocket for ARF1. One face of the C9orf72 domain holds ARF1 in place, while the SMCR8 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. |
 External links | Nat Commun / PubMed:34145292 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.94 Å |
| Structure data | EMDB-23827, PDB-7mge: |
| Chemicals |  ChemComp-GDP:  ChemComp-BEF:  ChemComp-MG: |
| Source |
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 Keywords |  TRANSPORT PROTEIN / complex / autophagy / ALS / GAP / small GTPase |
