当前位置: X-MOL 学术Sci. Adv. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Structural basis of purine nucleotide inhibition of human uncoupling protein 1
Science Advances ( IF 13.6 ) Pub Date : 2023-05-31 , DOI: 10.1126/sciadv.adh4251
Scott A Jones 1 , Prerana Gogoi 2 , Jonathan J Ruprecht 1 , Martin S King 1 , Yang Lee 1 , Thomas Zögg 3, 4 , Els Pardon 3, 4 , Deepak Chand 1 , Stefan Steimle 5 , Danielle M Copeman 6 , Camila A Cotrim 6 , Jan Steyaert 3, 4 , Paul G Crichton 6 , Vera Moiseenkova-Bell 2 , Edmund R S Kunji 1
Affiliation  

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.

中文翻译:

嘌呤核苷酸抑制人解偶联蛋白1的结构基础

线粒体解偶联蛋白 1 (UCP1) 使哺乳动物的棕色脂肪组织具有将卡路里燃烧为热量以进行体温调节的特殊能力。当被脂肪酸激活时,UCP1 会催化质子穿过线粒体内膜泄漏,使线粒体短路以产生热量,从而绕过 ATP 合成。相比之下,嘌呤核苷酸结合并抑制 UCP1,通过尚不清楚的分子机制调节质子泄漏。我们展示了 UCP1 的 GTP 抑制状态的冷冻电子显微镜结构,这与其非导电状态一致。嘌呤核苷酸通过广泛的相互作用网络交联 UCP1 的跨膜螺旋。我们的结果为理解调节机制的特异性和 pH 依赖性提供了结构基础。UCP1 保留了线粒体载体样运输机制所需的所有关键功能和结构特征。分析表明,抑制剂结合可防止 UCP1 用于促进质子泄漏的构象变化。
更新日期:2023-05-31
down
wechat
bug