Repository logo

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

Published version



Change log


Crichton, Paul G 
Lee, Yang 
Kunji, Edmund RS 


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.



Alternating access mechanism, Proton transport, Purine nucleotide inhibition, Thermogenesis, Adipocytes, 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

Journal Title


Conference Name

Journal ISSN


Volume Title



Elsevier BV
Medical Research Council (MC_U105663139)
Biotechnology and Biological Sciences Research Council (BB/R50564X/1)
Medical Research Council (MC_UU_00015/1)
Medical Research Council (MC_UU_00015/7)