日本研究人員在９日出版的美國(guó)《細(xì)胞生物學(xué)》雜志上報(bào)告說,，他們探明了肌體處理異常蛋白質(zhì)的機(jī)制，這將有助于找到新方法,，治療阿爾茨海默氏癥（早老性癡呆癥）等由異常蛋白質(zhì)堆積引發(fā)的疾病,。
日本奈良尖端科學(xué)技術(shù)研究生院大學(xué)的研究人員木俁行雄等發(fā)現(xiàn)，細(xì)胞內(nèi)有一種名為“Ｉｒｅ１”的感應(yīng)物質(zhì),，當(dāng)它檢測(cè)到結(jié)構(gòu)變形的異常蛋白質(zhì)的量增多時(shí),，就會(huì)發(fā)揮作用，促使名為“分子伴侶”的蛋白質(zhì)的合成量上升,，而“分子伴侶”蛋白質(zhì)能幫助異常蛋白質(zhì)的結(jié)構(gòu)恢復(fù)正常,。
這項(xiàng)研究使人們得以了解肌體處理異常蛋白質(zhì)的具體機(jī)制，并將有助于開發(fā)出用人為調(diào)節(jié)手段處理異常蛋白質(zhì)的方法,，從而為治療阿爾茨海默氏癥等疾病提供幫助,。（新華網(wǎng)）
原始出處：
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: [email protected] ; or Kenji Kohno: [email protected]
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.
