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Molecular mechanism of nucleotide inhibition of human uncoupling protein 1
Structural highlights
FunctionUCP1_HUMAN Mitochondrial protein responsible for thermogenic respiration, a specialized capacity of brown adipose tissue and beige fat that participates in non-shivering adaptive thermogenesis to temperature and diet variations and more generally to the regulation of energy balance (By similarity). Functions as a long-chain fatty acid/LCFA and proton symporter, simultaneously transporting one LCFA and one proton through the inner mitochondrial membrane (PubMed:24196960, PubMed:28781081). However, LCFAs remaining associated with the transporter via their hydrophobic tails, it results in an apparent transport of protons activated by LCFAs. Thereby, dissipates the mitochondrial proton gradient and converts the energy of substrate oxydation into heat instead of ATP. Regulates the production of reactive oxygen species/ROS by mitochondria (By similarity).[UniProtKB:P12242][1] [2] Publication Abstract from PubMedMitochondrial 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. Structural basis of purine nucleotide inhibition of human uncoupling protein 1.,Jones SA, Gogoi P, Ruprecht JJ, King MS, Lee Y, Zogg T, Pardon E, Chand D, Steimle S, Copeman DM, Cotrim CA, Steyaert J, Crichton PG, Moiseenkova-Bell V, Kunji ERS Sci Adv. 2023 Jun 2;9(22):eadh4251. doi: 10.1126/sciadv.adh4251. Epub 2023 May , 31. PMID:37256948[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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