TMEM120A, a member of the Transmembrane protein 120 (TMEM120) family, has pivotal function in adipocyte differentiation and metabolism, and may also contribute to sensing mechanical pain by functioning as an ion channel named TACAN. Here we report that expression of TMEM120A is not sufficient in mediating poking- or stretch-induced currents in cells, and have solved cryo-EM structures of human TMEM120A (HsTMEM120A) in complex with an endogenous metabolic cofactor (coenzyme A, CoASH) and in the apo form. HsTMEM120A forms a symmetrical homodimer with each monomer containing an amino-terminal coiled-coil motif followed by a transmembrane domain with six membrane-spanning helices. Within the transmembrane domain, a CoASH molecule is hosted in a deep cavity and forms specific interactions with nearby amino acid residues. Mutation of a central tryptophan residue involved in binding CoASH dramatically reduced the binding affinity of HsTMEM120A with CoASH. HsTMEM120A exhibits distinct conformations at the states with or without CoASH bound. Our results suggest that TMEM120A may have alternative functional roles potentially involved in CoASH transport, sensing or metabolism.

中文翻译：

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TMEM120A 包含特定的辅酶 A 结合位点，可能不会介导细胞中戳或拉伸诱导的通道活动

TMEM120A 是跨膜蛋白 120 (TMEM120) 家族的成员，在脂肪细胞分化和代谢中具有关键作用，并且还可能通过充当名为 TACAN 的离子通道来感知机械疼痛。在这里，我们报告 TMEM120A 的表达不足以介导细胞中的刺激或拉伸诱导的电流，并且已经解决了与内源性代谢辅因子（辅酶 A，CoASH）复合的人 TMEM120A（HsTMEM120A）的冷冻电镜结构和apo 形式。HsTMEM120A 形成一个对称的同源二聚体，每个单体包含一个氨基末端卷曲螺旋基序，然后是一个具有六个跨膜螺旋的跨膜结构域。在跨膜结构域内，CoASH 分子位于深腔中，并与附近的氨基酸残基形成特定的相互作用。参与结合 CoASH 的中央色氨酸残基的突变显着降低了 HsTMEM120A 与 CoASH 的结合亲和力。HsTMEM120A 在有或没有 CoASH 结合的状态下表现出不同的构象。我们的结果表明，TMEM120A 可能在 CoASH 转运、传感或代谢中具有潜在的替代功能。