Molecular mechanism of interactions between ACAD9 and binding partners in mitochondrial respiratory complex I assembly.
Biological sciences
Molecular biology
Structural biology
Journal
iScience
ISSN: 2589-0042
Titre abrégé: iScience
Pays: United States
ID NLM: 101724038
Informations de publication
Date de publication:
22 Oct 2021
22 Oct 2021
Historique:
received:
28
06
2021
revised:
09
08
2021
accepted:
16
09
2021
entrez:
14
10
2021
pubmed:
15
10
2021
medline:
15
10
2021
Statut:
epublish
Résumé
The dual function protein ACAD9 catalyzes α,β-dehydrogenation of fatty acyl-CoA thioesters in fatty acid β-oxidation and is an essential chaperone for mitochondrial respiratory complex I (CI) assembly. ACAD9, ECSIT, and NDUFAF1 interact to form the core mitochondrial CI assembly complex. Current studies examine the molecular mechanism of ACAD9/ECSIT/NDUFAF1interactions. ACAD9 binds to the carboxy-terminal half and NDUFAF1 to the amino-terminal half of ECSIT. Binary complexes are unstable and aggregate easily, while the ACAD9/ECSIT/NDUFAF1 ternary complex is soluble and highly stable. Molecular modeling and small-angle X-ray scattering studies identified intra-complex interaction sites and binding sites for other assembly factors. Binding of ECSIT at the ETF binding site in the amino-terminal domain of ACAD9 is consistent with observed loss of FAD and enzymatic activity and demonstrates that the two functions of ACAD9 are mutually exclusive. Mapping of 42 known pathogenic mutations onto the homology-modeled ACAD9 structure provides structural insights into pathomechanisms of CI deficiency.
Identifiants
pubmed: 34646991
doi: 10.1016/j.isci.2021.103153
pii: S2589-0042(21)01121-4
pmc: PMC8497999
doi:
Types de publication
Journal Article
Langues
eng
Pagination
103153Informations de copyright
© 2021 The Authors.
Déclaration de conflit d'intérêts
The authors declare no competing interests.
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