日本科學家在新一期美國《科學》雜志網(wǎng)絡版上介紹說，他們進一步探明了細胞處理缺陷蛋白質(zhì)的質(zhì)量控制機制,。這一成果可能有助于尋找治療阿爾茨海默氏癥等疾病的新方法。
日本京都大學教授永田和宏等人發(fā)現(xiàn),，細胞內(nèi)質(zhì)網(wǎng)上有3種蛋白質(zhì)巧妙分工合作,，檢測、分解并處理有缺陷的蛋白質(zhì),，承擔著對細胞內(nèi)的蛋白質(zhì)進行質(zhì)量管理的任務,。內(nèi)質(zhì)網(wǎng)是分布在細胞質(zhì)中的膜性管道系統(tǒng)，具有參與蛋白質(zhì)合成,、加工,、包裝等功能。
永田和宏等科學家此前曾發(fā)現(xiàn),，一種名為“EDEM”的蛋白質(zhì)能檢測出細胞內(nèi)有缺陷的蛋白質(zhì),，相當于細胞內(nèi)蛋白質(zhì)的“質(zhì)量總監(jiān)”。他們在新研究中又發(fā)現(xiàn),，“ERdj5”等另外兩種酶,，在處理缺陷蛋白質(zhì)的過程中也發(fā)揮著重要作用。
科學家說,，這兩種酶能拆開缺陷蛋白質(zhì),，使之成為一根細長的分子鏈，并把分子鏈運出內(nèi)質(zhì)網(wǎng),，進行廢棄處理,。其中，“ERdj5”是迄今發(fā)現(xiàn)的第一種能夠拆開缺陷蛋白質(zhì)中二硫鍵的酶,。拆開二硫鍵使得缺陷蛋白質(zhì)能夠被完全分解,，而且分解出的氨基酸還能再次用于合成其他蛋白質(zhì)。
基因異常等原因會導致機體錯誤地合成有缺陷的蛋白質(zhì),，這些蛋白質(zhì)如果在神經(jīng)等處堆積,，會引起阿爾茨海默氏癥和帕金森氏癥等疾病。永田和宏認為,，將來如果能夠依靠藥物激活細胞內(nèi)的質(zhì)量控制機制,，就有可能找到針對這些疾病的新療法。（生物谷Bioon.com）
生物谷推薦原始出處：
Science 25 July 2008:DOI: 10.1126/science.1159293
ERdj5 Is Required as a Disulfide Reductase for Degradation of Misfolded Proteins in the ER
Ryo Ushioda,1* Jun Hoseki,1,2* Kazutaka Araki,1* Gregor Jansen,3 David Y. Thomas,3 Kazuhiro Nagata1,2
Membrane and secretory proteins cotranslationally enter and are folded in the endoplasmic reticulum (ER). Misfolded or unassembled proteins are discarded by a process known as ER-associated degradation (ERAD), which involves their retrotranslocation into the cytosol. ERAD substrates frequently contain disulfide bonds that must be cleaved before their retrotranslocation. Here, we found that an ER-resident protein ERdj5 had a reductase activity, cleaved the disulfide bonds of misfolded proteins, and accelerated ERAD through its physical and functional associations with EDEM (ER degradation–enhancing -mannosidase–like protein) and an ER-resident chaperone BiP. Thus, ERdj5 is a member of a supramolecular ERAD complex that recognizes and unfolds misfolded proteins for their efficient retrotranslocation.
1 Department of Molecular and Cellular Biology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8397, Japan.
2 Core Research for Evolutional Science and Technology, Japan Science Technology Agency, Kawaguchi, Saitama 332-0012, Japan.
3 Biochemistry Department, Faculty of Medicine, McGill University, Montréal, Québec H3G 1Y6, Canada.
* These authors contributed equally to this work.
