The roles of SDHAF2 and dicarboxylate in covalent flavinylation of SDHA, the human complex II flavoprotein.
assembly
bioenergetics
complex II
flavinylation
protein folding
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
22 09 2020
22 09 2020
Historique:
pubmed:
6
9
2020
medline:
18
11
2020
entrez:
5
9
2020
Statut:
ppublish
Résumé
Mitochondrial complex II, also known as succinate dehydrogenase (SDH), is an integral-membrane heterotetramer (SDHABCD) that links two essential energy-producing processes, the tricarboxylic acid (TCA) cycle and oxidative phosphorylation. A significant amount of information is available on the structure and function of mature complex II from a range of organisms. However, there is a gap in our understanding of how the enzyme assembles into a functional complex, and disease-associated complex II insufficiency may result from incorrect function of the mature enzyme or from assembly defects. Here, we investigate the assembly of human complex II by combining a biochemical reconstructionist approach with structural studies. We report an X-ray structure of human SDHA and its dedicated assembly factor SDHAF2. Importantly, we also identify a small molecule dicarboxylate that acts as an essential cofactor in this process and works in synergy with SDHAF2 to properly orient the flavin and capping domains of SDHA. This reorganizes the active site, which is located at the interface of these domains, and adjusts the pK
Identifiants
pubmed: 32887801
pii: 2007391117
doi: 10.1073/pnas.2007391117
pmc: PMC7519310
doi:
Substances chimiques
Dicarboxylic Acids
0
Flavins
0
Mitochondrial Proteins
0
SDHAF2 protein, human
0
Transcription Factors
0
Electron Transport Complex II
EC 1.3.5.1
SDHA protein, human
EC 1.3.5.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
23548-23556Subventions
Organisme : BLRD VA
ID : IK6 BX004215
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM061606
Pays : United States
Déclaration de conflit d'intérêts
The authors declare no competing interest.
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