Structure of the C9orf72 ARF GAP complex that is haploinsufficient in ALS and FTD

Ming-Yuan Su; Simon A Fromm; Roberto Zoncu; James H Hurley

doi:10.1038/s41586-020-2633-x

Structure of the C9orf72 ARF GAP complex that is haploinsufficient in ALS and FTD

Nature. 2020 Sep;585(7824):251-255. doi: 10.1038/s41586-020-2633-x. Epub 2020 Aug 26.

Authors

Ming-Yuan Su^{1

2}, Simon A Fromm^{1

2}, Roberto Zoncu^{1

2}, James H Hurley^{3

4

5}

Affiliations

¹ Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.
² California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA, USA.
³ Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA. jimhurley@berkeley.edu.
⁴ California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA, USA. jimhurley@berkeley.edu.
⁵ Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA. jimhurley@berkeley.edu.

Abstract

Mutation of C9orf72 is the most prevalent defect associated with amyotrophic lateral sclerosis and frontotemporal degeneration¹. 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) domains⁷, and WDR41 is a β-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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adaptor Proteins, Signal Transducing / chemistry
Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism
Amyotrophic Lateral Sclerosis / genetics*
Amyotrophic Lateral Sclerosis / metabolism
Autophagy-Related Proteins / chemistry*
Autophagy-Related Proteins / deficiency
Autophagy-Related Proteins / metabolism
Autophagy-Related Proteins / ultrastructure
C9orf72 Protein / chemistry*
C9orf72 Protein / genetics*
C9orf72 Protein / metabolism
Carrier Proteins / chemistry*
Carrier Proteins / genetics
Carrier Proteins / metabolism
Carrier Proteins / ultrastructure
Cryoelectron Microscopy*
Frontotemporal Dementia / genetics*
Frontotemporal Dementia / metabolism
Haploinsufficiency*
Humans
Lysosomes / metabolism
Models, Molecular
Multiprotein Complexes / chemistry*
Multiprotein Complexes / genetics
Multiprotein Complexes / metabolism
Multiprotein Complexes / ultrastructure
Mutant Proteins / genetics
Mutant Proteins / metabolism
Mutation
Protein Domains

Substances

Adaptor Proteins, Signal Transducing
Autophagy-Related Proteins
C9orf72 Protein
C9orf72 protein, human
Carrier Proteins
Multiprotein Complexes
Mutant Proteins
SMCR8 protein, human
WDR41 protein, human

Supplementary concepts

Frontotemporal Dementia With Motor Neuron Disease

Abstract

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding