The molecular features of uncoupling protein 1 support a conventional mitochondrial carrier-like mechanism.

TitleThe molecular features of uncoupling protein 1 support a conventional mitochondrial carrier-like mechanism.
Publication TypeJournal Article
Year of Publication2017
AuthorsCrichton, PG, Lee, Y, Kunji, ERS
JournalBiochimie
Volume134
Pagination35-50
Date Published2017 Mar
ISSN1638-6183
KeywordsAdipocytes, Brown, Adipose Tissue, Brown, Animals, Cardiolipins, Energy Metabolism, Fatty Acids, Gene Expression Regulation, Humans, Ion Transport, Mitochondria, Models, Molecular, Protons, Purine Nucleotides, Thermogenesis, Uncoupling Protein 1
Abstract

Uncoupling protein 1 (UCP1) is an integral membrane protein found in the mitochondrial inner membrane of brown adipose tissue, and facilitates the process of non-shivering thermogenesis in mammals. Its activation by fatty acids, which overcomes its inhibition by purine nucleotides, leads to an increase in the proton conductance of the inner mitochondrial membrane, short-circuiting the mitochondrion to produce heat rather than ATP. Despite 40 years of intense research, the underlying molecular mechanism of UCP1 is still under debate. The protein belongs to the mitochondrial carrier family of transporters, which have recently been shown to utilise a domain-based alternating-access mechanism, cycling between a cytoplasmic and matrix state to transport metabolites across the inner membrane. Here, we review the protein properties of UCP1 and compare them to those of mitochondrial carriers. UCP1 has the same structural fold as other mitochondrial carriers and, in contrast to past claims, is a monomer, binding one purine nucleotide and three cardiolipin molecules tightly. The protein has a single substrate binding site, which is similar to those of the dicarboxylate and oxoglutarate carriers, but also contains a proton binding site and several hydrophobic residues. As found in other mitochondrial carriers, UCP1 has two conserved salt bridge networks on either side of the central cavity, which regulate access to the substrate binding site in an alternating way. The conserved domain structures and mobile inter-domain interfaces are consistent with an alternating access mechanism too. In conclusion, UCP1 has retained all of the key features of mitochondrial carriers, indicating that it operates by a conventional carrier-like mechanism.

DOI10.1016/j.biochi.2016.12.016
Alternate JournalBiochimie
Citation Key10.1016/j.biochi.2016.12.016
PubMed ID28057583
PubMed Central IDPMC5395090
Grant ListMC_U105663139 / / Medical Research Council / United Kingdom