In:
PLOS Biology, Public Library of Science (PLoS), Vol. 19, No. 7 ( 2021-7-23), p. e3001344-
Kurzfassung:
A major cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) spectrum disorder is the hexanucleotide G 4 C 2 repeat expansion in the first intron of the C9orf72 gene. Many underlying mechanisms lead to manifestation of disease that include toxic gain-of-function by repeat G 4 C 2 RNAs, dipeptide repeat proteins, and a reduction of the C9orf72 gene product. The C9orf72 protein interacts with SMCR8 and WDR41 to form a trimeric complex and regulates multiple cellular pathways including autophagy. Here, we report the structure of the C9orf72-SMCR8 complex at 3.8 Å resolution using single-particle cryo-electron microscopy (cryo-EM). The structure reveals 2 distinct dimerization interfaces between C9orf72 and SMCR8 that involves an extensive network of interactions. Homology between C9orf72-SMCR8 and Folliculin-Folliculin Interacting Protein 2 (FLCN-FNIP2), a GTPase activating protein (GAP) complex, enabled identification of a key residue within the active site of SMCR8. Further structural analysis suggested that a coiled-coil region within the uDenn domain of SMCR8 could act as an interaction platform for other coiled-coil proteins, and its deletion reduced the interaction of the C9orf72-SMCR8 complex with FIP200 upon starvation. In summary, this study contributes toward our understanding of the biological function of the C9orf72-SMCR8 complex.
Materialart:
Online-Ressource
ISSN:
1545-7885
DOI:
10.1371/journal.pbio.3001344
DOI:
10.1371/journal.pbio.3001344.g001
DOI:
10.1371/journal.pbio.3001344.g002
DOI:
10.1371/journal.pbio.3001344.g003
DOI:
10.1371/journal.pbio.3001344.g004
DOI:
10.1371/journal.pbio.3001344.g005
DOI:
10.1371/journal.pbio.3001344.g006
DOI:
10.1371/journal.pbio.3001344.s001
DOI:
10.1371/journal.pbio.3001344.s002
DOI:
10.1371/journal.pbio.3001344.s003
DOI:
10.1371/journal.pbio.3001344.s004
DOI:
10.1371/journal.pbio.3001344.s005
DOI:
10.1371/journal.pbio.3001344.s006
DOI:
10.1371/journal.pbio.3001344.s007
DOI:
10.1371/journal.pbio.3001344.s008
DOI:
10.1371/journal.pbio.3001344.s009
DOI:
10.1371/journal.pbio.3001344.s010
DOI:
10.1371/journal.pbio.3001344.s011
DOI:
10.1371/journal.pbio.3001344.s012
DOI:
10.1371/journal.pbio.3001344.s013
DOI:
10.1371/journal.pbio.3001344.s014
DOI:
10.1371/journal.pbio.3001344.s015
DOI:
10.1371/journal.pbio.3001344.s016
DOI:
10.1371/journal.pbio.3001344.s017
DOI:
10.1371/journal.pbio.3001344.r001
DOI:
10.1371/journal.pbio.3001344.r002
DOI:
10.1371/journal.pbio.3001344.r003
DOI:
10.1371/journal.pbio.3001344.r004
DOI:
10.1371/journal.pbio.3001344.r005
DOI:
10.1371/journal.pbio.3001344.r006
Sprache:
Englisch
Verlag:
Public Library of Science (PLoS)
Publikationsdatum:
2021
ZDB Id:
2126773-X
Permalink