Division of Signalling and Gene Expression, La Jolla Institute for Allergy & Immunology, La Jolla, CA, 92037, USA.
Instituto de Física de São Carlos, Universidade de São Paulo, São Carlos, CEP 13563-120, SP, Brazil.
Nat Commun. 2018 Oct 31;9(1):4536. doi: 10.1038/s41467-018-06816-8.
Stromal interaction molecule 1 (STIM1) monitors ER-luminal Ca levels to maintain cellular Ca balance and to support Ca signalling. The prevailing view has been that STIM1 senses reduced ER Ca through dissociation of bound Ca from a single EF-hand site, which triggers a dramatic loss of secondary structure and dimerization of the STIM1 luminal domain. Here we find that the STIM1 luminal domain has 5-6 Ca-binding sites, that binding at these sites is energetically coupled to binding at the EF-hand site, and that Ca dissociation controls a switch to a second structured conformation of the luminal domain rather than protein unfolding. Importantly, the other luminal-domain Ca-binding sites interact with the EF-hand site to control physiological activation of STIM1 in cells. These findings fundamentally revise our understanding of physiological Ca sensing by STIM1, and highlight molecular mechanisms that govern the Ca threshold for activation and the steep Ca concentration dependence.
基质相互作用分子 1（STIM1）通过监测内质网腔中的 Ca 水平来维持细胞内的 Ca 平衡并支持 Ca 信号转导。目前的观点认为，STIM1 通过从单个 EF 手型位点上解离结合的 Ca 来感知内质网中 Ca 的减少，这会触发 STIM1 腔结构域的二级结构显著丧失和二聚化。在这里，我们发现 STIM1 腔结构域有 5-6 个 Ca 结合位点，这些位点的结合与 EF 手型位点的结合在能量上是耦合的，而且 Ca 解离控制着腔结构域向第二种构象的转变，而不是蛋白质展开。重要的是，其他腔结构域 Ca 结合位点与 EF 手型位点相互作用，以控制细胞中 STIM1 的生理激活。这些发现从根本上修改了我们对 STIM1 进行生理 Ca 感应的理解，并强调了控制激活 Ca 阈值和陡峭的 Ca 浓度依赖性的分子机制。
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