PMID- 34297726
OWN - NLM
STAT- MEDLINE
DCOM- 20211108
LR  - 20211108
IS  - 1545-7885 (Electronic)
IS  - 1544-9173 (Print)
IS  - 1544-9173 (Linking)
VI  - 19
IP  - 7
DP  - 2021 Jul
TI  - Structure of the human C9orf72-SMCR8 complex reveals a multivalent protein 
      interaction architecture.
PG  - e3001344
LID - 10.1371/journal.pbio.3001344 [doi]
LID - e3001344
AB  - A major cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal 
      dementia (FTD) spectrum disorder is the hexanucleotide G4C2 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 G4C2 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 A 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.
FAU - Norpel, Julia
AU  - Norpel J
AUID- ORCID: 0000-0003-3025-8769
AD  - Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
AD  - University of Basel, Basel, Switzerland.
FAU - Cavadini, Simone
AU  - Cavadini S
AUID- ORCID: 0000-0003-2777-7584
AD  - Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
FAU - Schenk, Andreas D
AU  - Schenk AD
AUID- ORCID: 0000-0001-9214-2505
AD  - Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
FAU - Graff-Meyer, Alexandra
AU  - Graff-Meyer A
AUID- ORCID: 0000-0001-9312-9230
AD  - Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
FAU - Hess, Daniel
AU  - Hess D
AUID- ORCID: 0000-0002-1642-5404
AD  - Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
FAU - Seebacher, Jan
AU  - Seebacher J
AUID- ORCID: 0000-0002-7858-2720
AD  - Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
FAU - Chao, Jeffrey A
AU  - Chao JA
AUID- ORCID: 0000-0002-5895-9156
AD  - Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
FAU - Bhaskar, Varun
AU  - Bhaskar V
AD  - Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210723
PL  - United States
TA  - PLoS Biol
JT  - PLoS biology
JID - 101183755
RN  - 0 (C9orf72 Protein)
RN  - 0 (Carrier Proteins)
RN  - 0 (SMCR8 protein, human)
RN  - Amyotrophic lateral sclerosis 1
SB  - IM
MH  - Amyotrophic Lateral Sclerosis/genetics
MH  - Animals
MH  - C9orf72 Protein/genetics/*metabolism
MH  - Carrier Proteins/chemistry/genetics/*metabolism
MH  - Cell Line
MH  - Frontotemporal Dementia/genetics
MH  - Humans
MH  - Molecular Structure
MH  - Open Reading Frames
MH  - Protein Binding
MH  - Protein Interaction Maps
MH  - Spodoptera
PMC - PMC8336837
COIS- The authors have declared that no competing interests exist.
EDAT- 2021/07/24 06:00
MHDA- 2021/11/09 06:00
PMCR- 2021/07/23
CRDT- 2021/07/23 17:17
PHST- 2020/09/03 00:00 [received]
PHST- 2021/07/01 00:00 [accepted]
PHST- 2021/08/04 00:00 [revised]
PHST- 2021/07/24 06:00 [pubmed]
PHST- 2021/11/09 06:00 [medline]
PHST- 2021/07/23 17:17 [entrez]
PHST- 2021/07/23 00:00 [pmc-release]
AID - PBIOLOGY-D-20-02662 [pii]
AID - 10.1371/journal.pbio.3001344 [doi]
PST - epublish
SO  - PLoS Biol. 2021 Jul 23;19(7):e3001344. doi: 10.1371/journal.pbio.3001344. 
      eCollection 2021 Jul.