Structural basis of purine nucleotide inhibition of human uncoupling protein 1

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 gene...

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Published in:Science advances 2023-06, Vol.9 (22), p.eadh4251-eadh4251
Main Authors: 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, Moiseenkova-Bell, Vera, Kunji, Edmund R S
Format: Article
Language:English
Subjects:
Biomedicine and Life Sciences
Biophysics
Cryoelectron Microscopy
Humans
Ion Channels - chemistry
Mitochondrial Proteins - metabolism
Protons
Purine Nucleotides
SciAdv r-articles
Structural Biology
Uncoupling Protein 1 - genetics
Uncoupling Protein 1 - metabolism
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Summary: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.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.adh4251