日本研究人员在９日出版的美国《细胞生物学》杂志上报告说，他们探明了肌体处理异常蛋白质的机制，这将有助于找到新方法，治疗阿尔茨海默氏症（早老性痴呆症）等由异常蛋白质堆积引发的疾病。
日本奈良尖端科学技术研究生院大学的研究人员木俣行雄等发现，细胞内有一种名为“Ｉｒｅ１”的感应物质，当它检测到结构变形的异常蛋白质的量增多时，就会发挥作用，促使名为“分子伴侣”的蛋白质的合成量上升，而“分子伴侣”蛋白质能帮助异常蛋白质的结构恢复正常。
这项研究使人们得以了解肌体处理异常蛋白质的具体机制，并将有助于开发出用人为调节手段处理异常蛋白质的方法，从而为治疗阿尔茨海默氏症等疾病提供帮助。（新华网）
原始出处：
Published online 8 October 2007
doi:10.1083/jcb.200704166
The Journal of Cell Biology, Vol. 179, No. 1, 75-86
Two regulatory steps of ER-stress sensor Ire1 involving its cluster formation and interaction with unfolded proteins
Yukio Kimata1, Yuki Ishiwata-Kimata1, Tatsuhiko Ito1, Aiko Hirata2, Tomohide Suzuki1, Daisuke Oikawa1, Masato Takeuchi1, and Kenji Kohno1
1 Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Nara 630-0192, Japan
2 Department of Integrated Biosciences, Graduate School of Frontier Sciences, the University of Tokyo, Kashiwa, Chiba 277-8562, Japan
Correspondence to Yukio Kimata: kimata@zero.ad.jp ; or Kenji Kohno: kkouno@bs.naist.jp
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.
Abbreviations used in this paper: CSSR, core stress-sensing region; IP, immunoprecipitate; MBP, maltose binding protein; MHC, major histocompatibility complex; PERK, pancreatic ER kinase; Tun, Tunicamycin; UPR, unfolded protein response; UPRE, UPR element.
