Structural basis of purine nucleotide inhibition of human uncoupling protein 1

Jones, Scott A., Gogoi, Prerana, Ruprecht, Jonathan J., King, Martin S., Lee, Yang, Zögg, Thomas, Pardon, Els, Chand, Deepak, Steimle, Stefan, Copeman, Danielle M., Cotrim, Camila A., Steyaert, Jan, Crichton, Paul G. ORCID:, Moiseenkova-Bell, Vera and Kunji, Edmund R. S. (2023) Structural basis of purine nucleotide inhibition of human uncoupling protein 1. Science Advances, 9 (22). ISSN 2375-2548

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Mitochondrial uncoupling protein 1 (UCP1) gives brown adipose tissue of mammals its specialized ability to burn calories as heat for thermoregulation. When activated by fatty acids, UCP1 catalyzes the leak of protons across the mitochondrial inner membrane, short-circuiting the mitochondrion to generate heat, bypassing ATP synthesis. In contrast, purine nucleotides bind and inhibit UCP1, regulating proton leak by a molecular mechanism that is unclear. We present the cryo–electron microscopy structure of the GTP-inhibited state of UCP1, which is consistent with its nonconducting state. The purine nucleotide cross-links the transmembrane helices of UCP1 with an extensive interaction network. Our results provide a structural basis for understanding the specificity and pH dependency of the regulatory mechanism. UCP1 has retained all of the key functional and structural features required for a mitochondrial carrier–like transport mechanism. The analysis shows that inhibitor binding prevents the conformational changes that UCP1 uses to facilitate proton leak.

Item Type: Article
Additional Information: Funding Information: National Institute of General Medical Sciences: 5R35GM144120; Medical Research Council: MC_UU_00028/2; Medical Research Council: MC_UU_00015/1; UK Biological and Biotechnological Sciences Research Council: BB/S00940X/1; European Strategy Forum on Research infrastructure; Research Foundation Flanders; Strategic Research Program of the Free University of Brussels
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups: Faculty of Medicine and Health Sciences > Research Groups > Cardiovascular and Metabolic Health
Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health
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Depositing User: LivePure Connector
Date Deposited: 01 Jun 2023 14:30
Last Modified: 19 Oct 2023 03:36
DOI: 10.1126/sciadv.adh4251


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