Accumulation of unfolded proteins in the endoplasmic reticulum (ER) accompanies ER stress and causes the type-I transmembarane protein Ire1 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 no or weak stress conditions. 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 carry N-terminal intrinsically disordered subdomains with a similar structure and function as 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.
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