Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322.
Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, NY 10065.
Proc Natl Acad Sci U S A. 2020 Sep 8;117(36):22080-22089. doi: 10.1073/pnas.2003877117. Epub 2020 Aug 20.
Nonshivering thermogenesis occurs in brown adipose tissue to generate heat in response to cold ambient temperatures. Thioesterase superfamily member 1 (Them1) is transcriptionally up-regulated in brown adipose tissue upon exposure to the cold and suppresses thermogenesis in order to conserve energy reserves. It hydrolyzes long-chain fatty acyl-CoAs that are derived from lipid droplets, preventing their use as fuel for thermogenesis. In addition to its enzymatic domains, Them1 contains a C-terminal StAR-related lipid transfer (START) domain with unknown ligand or function. By complementary biophysical approaches, we show that the START domain binds to long-chain fatty acids, products of Them1's enzymatic reaction, as well as lysophosphatidylcholine (LPC), lipids shown to activate thermogenesis in brown adipocytes. Certain fatty acids stabilize the START domain and allosterically enhance Them1 catalysis of acyl-CoA, whereas 18:1 LPC destabilizes and inhibits activity, which we verify in cell culture. Additionally, we demonstrate that the START domain functions to localize Them1 near lipid droplets. These findings define the role of the START domain as a lipid sensor that allosterically regulates Them1 activity and spatially localizes it in proximity to the lipid droplet.
非颤抖性产热发生在棕色脂肪组织中，以响应寒冷的环境温度产生热量。硫酯酶超家族成员 1（Them1）在暴露于寒冷时在棕色脂肪组织中被转录上调，并抑制产热以保存能量储备。它水解源自脂质滴的长链脂肪酸酰基辅酶 A，防止它们被用作产热的燃料。除了其酶结构域外，Them1 还包含一个 C 端与星状相关的脂质转移（START）结构域，其配体或功能未知。通过互补的生物物理方法，我们表明 START 结构域结合长链脂肪酸，这是 Them1 酶反应的产物，以及溶血磷脂酰胆碱（LPC），这些脂质已被证明可激活棕色脂肪细胞中的产热。某些脂肪酸稳定 START 结构域并变构增强 Them1 对酰基辅酶 A 的催化作用，而 18:1 LPC 则使其失稳并抑制活性，这在细胞培养中得到了验证。此外，我们证明 START 结构域的功能是将 Them1 定位在脂质滴附近。这些发现定义了 START 结构域作为脂质传感器的作用，它变构调节 Them1 活性并将其空间定位在接近脂质滴的位置。
