Tight regulation of the unfolded protein sensor Ire1 by its intramolecularly antagonizing subdomain
Tight regulation of the unfolded protein sensor Ire1 by its intramolecularly antagonizing subdomain
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DOI：
10.1242/jcs.164111
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发表时间：
2015-05-01
影响因子：
4
通讯作者：
Kimata, Yukio
中科院分区：
文献类型：
--
作者：
Mathuranyanon, Rubwad;Tsukamoto, Tomoko;Kimata, Yukio
内质网（ER）中未折叠蛋白的积累伴随着ER应激，并导致I型跨膜蛋白Ire 1（也称为ERN 1）触发未折叠蛋白反应（UPR）。当二聚化时，Ire 1的核心应力敏感区（CSSR）直接捕获未折叠的蛋白质并形成高阶寡聚体，导致Ire 1的聚集和激活。在酿酒酵母Ire 1中，CSSR的N-末端两侧是一个内在无序的亚结构域，我们以前将其命名为亚区I。在这项研究中，我们描述了严格的镇压IRE 1活动的亚区I的条件下，没有或弱应力。弱超活化的Ire 1突变缺乏亚区I轻微延缓酵母细胞在无应激条件下培养的生长。真菌Ire 1直系同源物和动物Ire 1家族蛋白PERK（也称为EIF 2AK 3）携带N-末端固有无序亚结构域，其结构和功能与亚区I相似。我们在这里提出的观察结果累积表明，亚区I被捕获的CSSR作为一个未折叠的蛋白质底物。这种分子内亚结构域的相互作用可能会损害CSSR的自相关性，这解释了为什么当ER积累的未折叠蛋白不丰富时，亚区域I可以抑制Ire 1活性。
Accumulation of unfolded proteins in the endoplasmic reticulum (ER) accompanies ER stress and causes the type-I transmembrane protein Ire1 (also known as ERN1) to trigger the unfolded protein response (UPR). When dimerized, the core stress-sensing region (CSSR) of Ire1 directly captures unfolded proteins and forms a high-order oligomer, leading to clustering and activation of Ire1. The CSSR is N-terminally flanked by an intrinsically disordered subdomain, which we previously named Subregion I, in Saccharomyces cerevisiae Ire1. In this study, we describe tight repression of Ire1 activity by Subregion I under conditions of no or weak stress. Weak hyperactivation of an Ire1 mutant lacking Subregion I slightly retarded growth of yeast cells cultured under unstressed conditions. Fungal Ire1 orthologs and the animal Ire1 family protein PERK (also known as EIF2AK3) carry N-terminal intrinsically disordered subdomains with a similar structure and function to that of Subregion I. Our observations presented here cumulatively indicate that Subregion I is captured by the CSSR as an unfolded protein substrate. This intramolecular subdomain interaction is likely to compromise self-association of the CSSR, explaining why Subregion I can suppress Ire1 activity when ER-accumulated unfolded proteins are not abundant.