Kimata Yukio, Ishiwata-Kimata Yuki, Ito Tatsuhiko, Hirata Aiko, Suzuki Tomohide, Oikawa Daisuke, Takeuchi Masato, Kohno Kenji
Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Nara 630-0192, Japan.
J Cell Biol. 2007 Oct 8;179(1):75-86. doi: 10.1083/jcb.200704166.
Chaperone protein BiP binds to Ire1 and dissociates in response to endoplasmic reticulum (ER) stress. However, it remains unclear how the signal transducer Ire1 senses ER stress and is subsequently activated. The crystal structure of the core stress-sensing region (CSSR) of yeast Ire1 luminal domain led to the controversial suggestion that the molecule can bind to unfolded proteins. We demonstrate that, upon ER stress, Ire1 clusters and actually interacts with unfolded proteins. Ire1 mutations that affect these phenomena reveal that Ire1 is activated via two steps, both of which are ER stress regulated, albeit in different ways. In the first step, BiP dissociation from Ire1 leads to its cluster formation. In the second step, direct interaction of unfolded proteins with the CSSR orients the cytosolic effector domains of clustered Ire1 molecules.
伴侣蛋白BiP与Ire1结合，并在内质网（ER）应激反应中解离。然而，信号转导分子Ire1如何感知ER应激并随后被激活仍不清楚。酵母Ire1腔结构域的核心应激感应区域（CSSR）的晶体结构引发了关于该分子可与未折叠蛋白结合的争议性观点。我们证明，在ER应激时，Ire1聚集并实际上与未折叠蛋白相互作用。影响这些现象的Ire1突变表明，Ire1通过两个步骤被激活，这两个步骤均受ER应激调节，尽管方式不同。第一步，BiP从Ire1上解离导致其聚集形成。第二步，未折叠蛋白与CSSR的直接相互作用使聚集的Ire1分子的胞质效应结构域定向。
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