Structure of the C9orf72 Arf GAP complex haploinsufficient in ALS and FTD

Mutation of C9ORF72 is the most prevalent defect in amyotrophic lateral sclerosis (ALS) and frontal temporal degeneration (FTD)(1). Together with hexanucleotide repeat expansion(2,3), haploinsufficiency of C9ORF72 contributes to neuronal dysfunction(4–6). We determined the structure of the C9orf72-SMCR8-WDR41 complex by cryo-EM. C9orf72 and SMCR8 are both longin-DENN domain proteins(7), while WDR41 is a beta-propeller protein that binds to SMCR8 such that the whole structure resembles an eye slip hook. Contacts between WDR41 and SMCR8(DENN) drive lysosomal localization in amino acid starvation. The structure suggested that C9orf72-SMCR8 was a small GTPase activating protein (GAP). We found that C9orf72-SMCR8-WDR41 is a GAP for Arf family small GTPases. These data rationalize the function of C9orf72 both in normal physiology and in ALS/FTD.