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

Abstract

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.

Melatonin increases brown adipose tissue mass and function in Zücker diabetic fatty rats: implications for obesity control

“…This is accomplished by the uncoupling protein UCP1 (thermogenin) which is selectively expressed in brown adipocytes. UCP1 is a 32 kDa polypeptide that belongs to the ion carrier protein family, located in the inner membrane of the mitochondria . By transporting protons (H + ) back into the mitochondrial matrix, UCP1 renders the inner membrane of mitochondria leaky, thereby diverting chemical energy from ATP synthesis to heat production .…”

“…UCP1 also specifically binds, but is inhibited by cytosolic purine nucleotides (ATP, ADP, GTP, and GDP), ATP and ADP being physiologically the most relevant. Purine nucleotides inhibit UCP1 with high affinity by binding from the cytosolic side in a 1:1 inhibitor:protein stoichiometry . Guanosine diphosphate (GDP) binding has been universally adopted as an assay of functional UCP1 because of its high affinity and its lack of side effects on the mitochondria …”

“…UCP1 is a 32 kDa polypeptide that belongs to the ion carrier protein family, located in the inner membrane of the mitochondria. 2 By transporting protons (H + ) back into the mitochondrial matrix, UCP1 renders the inner membrane of mitochondria leaky, thereby diverting chemical energy from ATP synthesis to heat production. 1,3 The amount of UCP1 is considered an index of the thermogenic capacity of BAT.…”

“…Purine nucleotides inhibit UCP1 with high affinity by binding from the cytosolic side in a 1:1 inhibitor:protein stoichiometry. 2 Guanosine diphosphate (GDP) binding has been universally adopted as an assay of functional UCP1 because of its high affinity and its lack of side effects on the mitochondria. 3 Melatonin is a molecule produced at night by the vertebrate pineal gland 4,5 and in many other tissues as well.…”

Effects of nicotine on homeostatic and hedonic components of food intake

“…When activated, UCP1 allows protons in the intermembrane space to re-enter the mitochondrial matrix without generating ATP. As a consequence, heat is generated from the combustion of available substrates and is distributed to the rest of the body through the circulation (Vosselman, van Marken Lichtenbelt et al 2013; Contreras, Nogueiras et al 2017; Crichton, Lee et al 2017; Porter 2017). …”