Department of Biochemistry, Weill Cornell Medical School, New York, NY.
Department of Anesthesiology, Weill Cornell Medical School, New York, NY.
J Gen Physiol. 2018 Jul 2;150(7):933-947. doi: 10.1085/jgp.201711957. Epub 2018 Jun 18.
The TMEM16 family of membrane proteins is composed of both Ca-gated Cl channels and Ca-dependent phospholipid scramblases. The functional diversity of TMEM16s underlies their involvement in numerous signal transduction pathways that connect changes in cytosolic Ca levels to cellular signaling networks. Indeed, defects in the function of several TMEM16s cause a variety of genetic disorders, highlighting their fundamental pathophysiological importance. Here, we review how our mechanistic understanding of TMEM16 function has been shaped by recent functional and structural work. Remarkably, the recent determination of near-atomic-resolution structures of TMEM16 proteins of both functional persuasions has revealed how relatively minimal rearrangements in the substrate translocation pathway are sufficient to precipitate the dramatic functional differences that characterize the family. These structures, when interpreted in the light of extensive functional analysis, point to an unusual mechanism for Ca-dependent activation of TMEM16 proteins in which substrate permeation is regulated by a combination of conformational rearrangements and electrostatics. These breakthroughs pave the way to elucidate the mechanistic bases of ion and lipid transport by the TMEM16 proteins and unravel the molecular links between these transport activities and their function in human pathophysiology.
TMEM16 家族的膜蛋白由钙门控氯离子通道和钙依赖性磷脂翻转酶组成。TMEM16s 的功能多样性是它们参与众多信号转导途径的基础，这些途径将细胞溶质 Ca 水平的变化与细胞信号网络连接起来。事实上，几种 TMEM16 功能的缺陷导致了多种遗传疾病，突出了它们在基础病理生理学中的重要性。在这里，我们回顾了我们对 TMEM16 功能的机制理解是如何受到最近的功能和结构研究的影响的。值得注意的是，最近对具有两种功能倾向的 TMEM16 蛋白的近原子分辨率结构的测定揭示了底物转运途径中相对较小的重排如何足以引发家族特征的显著功能差异。这些结构，当结合广泛的功能分析进行解释时，指向了一种 TMEM16 蛋白的钙依赖性激活的不寻常机制，其中底物渗透受构象重排和静电的组合调节。这些突破为阐明 TMEM16 蛋白的离子和脂质转运的机制基础铺平了道路，并揭示了这些转运活性与其在人类病理生理学中的功能之间的分子联系。
