Structural insights into G domain dimerization and pathogenic mutation of OPA1.
Beryllium
/ chemistry
Binding Sites
Cloning, Molecular
Crystallography, X-Ray
Escherichia coli
/ genetics
Fluorides
/ chemistry
GTP Phosphohydrolases
/ chemistry
Gene Expression
Genetic Vectors
/ chemistry
Guanosine Diphosphate
/ chemistry
Humans
Liposomes
/ chemistry
Magnesium
/ chemistry
Models, Molecular
Mutation
Optic Atrophy
/ enzymology
Potassium
/ chemistry
Protein Binding
Protein Conformation, alpha-Helical
Protein Conformation, beta-Strand
Protein Interaction Domains and Motifs
Protein Multimerization
Recombinant Proteins
/ chemistry
Journal
The Journal of cell biology
ISSN: 1540-8140
Titre abrégé: J Cell Biol
Pays: United States
ID NLM: 0375356
Informations de publication
Date de publication:
06 07 2020
06 07 2020
Historique:
received:
15
07
2019
revised:
18
02
2020
accepted:
19
04
2020
entrez:
8
5
2020
pubmed:
8
5
2020
medline:
18
3
2021
Statut:
ppublish
Résumé
The fusion of mammalian inner mitochondrial membranes (IMMs) is mediated by dynamin-like GTPase OPA1. Mutations in human OPA1 cause optic atrophy, but the molecular basis for membrane fusion and pathogenesis is not clear. Here, we determined the crystal structure of the minimal GTPase domain (MGD) of human OPA1. A three-helix bundle (HB) domain including two helices extending from the GTPase (G) domain and the last helix of OPA1 tightly associates with the G domain. In the presence of GDP and BeF3-, OPA1-MGD forms a dimer, the interface of which is critical for the maintenance of mitochondrial morphology. The catalytic core of OPA1 possesses unique features that are not present in other dynamin-like proteins. Biochemical experiments revealed that OPA1-MGD forms nucleotide-dependent dimers, which is important for membrane-stimulated GTP hydrolysis, and an N-terminal extension mediates nucleotide-independent dimerization that facilitates efficient membrane association. Our results suggest a multifaceted assembly of OPA1 and explain the effect of most OPA1 mutations on optic atrophy.
Identifiants
pubmed: 32379273
pii: 151743
doi: 10.1083/jcb.201907098
pmc: PMC7337494
pii:
doi:
Substances chimiques
Liposomes
0
Recombinant Proteins
0
Guanosine Diphosphate
146-91-8
beryllium fluoride
499FU9DQ5C
GTP Phosphohydrolases
EC 3.6.1.-
OPA1 protein, human
EC 3.6.1.-
Magnesium
I38ZP9992A
Beryllium
OW5102UV6N
Fluorides
Q80VPU408O
Potassium
RWP5GA015D
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2020 Yu et al.
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