Structural basis for the ARF GAP activity and specificity of the C9orf72 complex
Copyright policy )Structural basis for the ARF GAP activity and specificity of the C9orf72 complex
AbstractMutation ofC9ORF72is 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-BeF3-bound to C9orf72:SMCR8:WDR41. The SMCR8longinand C9orf72longindomains form the binding pocket for ARF1. One face of the C9orf72longindomain holds ARF1 in place, while the SMCR8longinpositions 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.
- Southwest University of Science and Technology China (People's Republic of)
- University of California System United States
- University of California, San Francisco United States
- QB3 United States
- University of California, Berkeley United States
Aging, Protein Structure, 1.1 Normal biological development and functioning, Science, 610, Autophagy-Related Proteins, Neurodegenerative, Mechanistic Target of Rapamycin Complex 1, Article, Rare Diseases, Acquired Cognitive Impairment, Genetics, 2.1 Biological and endogenous factors, Humans, Alzheimer's Disease Related Dementias (ADRD), C9orf72 Protein, Q, Amyotrophic Lateral Sclerosis, Cryoelectron Microscopy, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Biological Sciences, Brain Disorders, Protein Structure, Tertiary, Frontotemporal Dementia (FTD), rab GTP-Binding Proteins, Frontotemporal Dementia, Multiprotein Complexes, Neurological, Dementia, ADP-Ribosylation Factor 1, Biochemistry and Cell Biology, ALS, Carrier Proteins, Tertiary
Aging, Protein Structure, 1.1 Normal biological development and functioning, Science, 610, Autophagy-Related Proteins, Neurodegenerative, Mechanistic Target of Rapamycin Complex 1, Article, Rare Diseases, Acquired Cognitive Impairment, Genetics, 2.1 Biological and endogenous factors, Humans, Alzheimer's Disease Related Dementias (ADRD), C9orf72 Protein, Q, Amyotrophic Lateral Sclerosis, Cryoelectron Microscopy, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Biological Sciences, Brain Disorders, Protein Structure, Tertiary, Frontotemporal Dementia (FTD), rab GTP-Binding Proteins, Frontotemporal Dementia, Multiprotein Complexes, Neurological, Dementia, ADP-Ribosylation Factor 1, Biochemistry and Cell Biology, ALS, Carrier Proteins, Tertiary
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