The molecular features of uncoupling protein 1 support a conventional mitochondrial carrier-like mechanism.
The molecular features of uncoupling protein 1 support a conventional mitochondrial carrier-like mechanism.
复制标题
DOI：
10.1016/j.biochi.2016.12.016
复制
发表时间：
2017-03
期刊：
影响因子：
3.9
通讯作者：
Kunji ER
中科院分区：
文献类型：
--
作者：
Crichton PG;Lee Y;Kunji ER
解偶联蛋白1（UCP1）是存在于棕色脂肪组织线粒体内膜中的一种膜蛋白，促进哺乳动物非颤抖性产热过程。它被脂肪酸激活，克服了嘌呤核苷酸的抑制作用，导致线粒体内膜的质子电导增加，使线粒体短路产生热量而不是ATP。尽管经过40年的深入研究，UCP1的潜在分子机制仍存在争议。该蛋白属于转运蛋白的线粒体载体家族，其最近被证明利用基于结构域的交替进入机制，在细胞质和基质状态之间循环以跨内膜转运代谢物。在这里，我们回顾了UCP1的蛋白质特性，并将其与线粒体载体的蛋白质特性进行比较。UCP1具有与其他线粒体载体相同的结构折叠，并且与过去的声明相反，UCP1是单体，紧密结合一个嘌呤核苷酸和三个心磷脂分子。该蛋白质具有单个底物结合位点，与二羧酸和氧戊二酸载体的结合位点相似，但还含有质子结合位点和几个疏水性残基。与其他线粒体载体一样，UCP1在中央腔的两侧有两个保守的盐桥网络，它们以交替的方式调节底物结合位点的进入。保守的域结构和移动的域间接口也与交替访问机制一致。总之，UCP1保留了线粒体载体的所有关键特征，表明它通过传统的载体样机制运作。
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.