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

Crichton, Paul G., Lee, Yang and Kunji, Edmund R. S. (2017) The molecular features of uncoupling protein 1 support a conventional mitochondrial carrier-like mechanism. Biochimie, 134. 35–50. ISSN 0300-9084

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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 GDP 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.

Item Type: Article
Additional Information: © 2017 Medical Research Council. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (
Uncontrolled Keywords: thermogenesis,proton transport,purine nucleotide inhibition,alternating access mechanism
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
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Depositing User: Pure Connector
Date Deposited: 13 Jan 2017 00:06
Last Modified: 11 Apr 2022 10:30
DOI: 10.1016/j.biochi.2016.12.016

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