title: Tight regulation of the unfolded protein sensor Ire1 by its intramolecularly antagonizing subdomain.
abstract: 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.
authors.affiliation: Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0192, Japan.
authors.forename: Rubwad
authors.initials: R
authors.lastname: Mathuranyanon
authors.affiliation: Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0192, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Tsukamoto
authors.affiliation: Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0192, Japan.
authors.forename: Asumi
authors.initials: A
authors.lastname: Takeuchi
authors.affiliation: Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0192, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ishiwata-Kimata
authors.affiliation: Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0192, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Tsuchiya
authors.affiliation: Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0192, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kohno
authors.affiliation: Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0192, Japan kimata@bs.naist.jp.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kimata
mesh_terms: D000818:Animals; D008322:Mammals; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000378:metabolism*; D051379:Mice; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D041681:NIH 3T3 Cells; D010455:Peptides / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry* / Q000378:metabolism*; D017384:Sequence Deletion; D013997:Time Factors; D020798:Two-Hybrid System Techniques; D056811:Unfolded Protein Response; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D008562:Membrane Glycoproteins; D050505:Mutant Proteins; D010455:Peptides; D017346:Protein Serine-Threonine Kinases; D029701:Saccharomyces cerevisiae Proteins; D019892:eIF-2 Kinase; C082863:IRE1 protein, S cerevisiae
keywords: Endoplasmic reticulum; Intrinsically disordered region; Misfolded protein; Molecular chaperone; Stress response; Unfolded protein response