Assembly of the membrane domain of ATP synthase in human mitochondria

The ATP synthase in human mitochondria is a membrane-bound assembly of 29 proteins of 18 kinds. All but two membrane components are encoded in nuclear genes, synthesized on cytoplasmic ribosomes, and imported into the matrix of the organelle, where they are assembled into the complex with ATP6 and A...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2018-03, Vol.115 (12), p.2988-2993
Main Authors: He, Jiuya, Ford, Holly C., Carroll, Joe, Douglas, Corsten, Gonzales, Evvia, Ding, Shujing, Fearnley, Ian M., Walker, John E.
Format: Article
Language:English
Subjects:
Adenosine triphosphatase
Adenosine triphosphate
Assembly
ATP
ATP synthase
Biological Sciences
Cell Line
Cell Proliferation
Coding
CRISPR-Cas Systems
Cristae
Cytoplasm
Deoxyribonucleic acid
Diabetes mellitus
Dimers
DNA
Gene Expression Regulation, Enzymologic
Genes
Humans
Insulin
Locks
Membranes
Mitochondria
Mitochondrial DNA
Mitochondrial Membranes - enzymology
Mitochondrial Proton-Translocating ATPases - genetics
Mitochondrial Proton-Translocating ATPases - metabolism
Models, Molecular
Mutation
Oligomers
Oxygen Consumption
Protein Conformation
Protein Subunits
Proteins
Ribosomes
Synthesis
Yeast
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Summary:The ATP synthase in human mitochondria is a membrane-bound assembly of 29 proteins of 18 kinds. All but two membrane components are encoded in nuclear genes, synthesized on cytoplasmic ribosomes, and imported into the matrix of the organelle, where they are assembled into the complex with ATP6 and ATP8, the products of overlapping genes in mitochondrial DNA. Disruption of individual human genes for the nuclear-encoded subunits in the membrane portion of the enzyme leads to the formation of intermediate vestigial ATPase complexes that provide a description of the pathway of assembly of the membrane domain. The key intermediate complex consists of the F₁-c₈ complex inhibited by the ATPase inhibitor protein IF₁ and attached to the peripheral stalk, with subunits e, f, and g associated with the membrane domain of the peripheral stalk. This intermediate provides the template for insertion of ATP6 and ATP8, which are synthesized on mitochondrial ribosomes. Their association with the complex is stabilized by addition of the 6.8 proteolipid, and the complex is coupled to ATP synthesis at this point. A structure of the dimeric yeast Fₒ membrane domain is consistent with this model of assembly. The human 6.8 proteolipid (yeast j subunit) locks ATP6 and ATP8 into the membrane assembly, and the monomeric complexes then dimerize via interactions between ATP6 subunits and between 6.8 proteolipids (j subunits). The dimers are linked together back-to-face by DAPIT (diabetes-associated protein in insulin-sensitive tissue; yeast subunit k), forming long oligomers along the edges of the cristae.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1722086115