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Cited by 0Endoplasmic Reticulum Stress and DiseaseProtein Structure and DynamicsIon Channels and Receptors

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Structural dynamics of IRE1 and its interaction with unfolded peptides

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Spinetti, Elena, Ścibisz, Grzegorz, Karagöz, Gülsün Elif, Covino, Roberto·2026·eLife
DOI 10.7554/elife.106716

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Abstract

The unfolded protein response (UPR) is a crucial signaling network that preserves endoplasmic reticulum (ER) homeostasis, impacting both health and disease. When ER stress occurs, often due to an accumulation of unfolded proteins in the ER lumen, the UPR initiates a broad cellular program to counteract cytotoxic effects. Inositol-requiring enzyme 1 (IRE1), a conserved ER-bound protein, is a key sensor of ER stress and activator of the UPR. While biochemical studies confirm IRE1’s role in recognizing unfolded polypeptides, high-resolution structures showing direct interactions remain elusive. Consequently, the precise structural mechanism by which IRE1 senses unfolded proteins is debated. In this study, we employed advanced molecular modeling and 137 µs of atomistic molecular dynamics simulations to clarify how IRE1 detects unfolded proteins. Our results demonstrate that IRE1’s luminal domain directly interacts with unfolded peptides and reveal how these interactions can stabilize higher-order oligomers. We provide a detailed molecular characterization of unfolded peptide binding, identifying two distinct binding pockets at the dimer’s center, separate from its central groove. Furthermore, we present high-resolution structures illustrating how BiP associates with IRE1’s oligomerization interface, thus preventing the formation of larger complexes. Our structural model reconciles seemingly contradictory experimental findings, offering a unified perspective on the diverse sensing models proposed. We elucidate the structural dynamics of unfolded protein sensing by IRE1, providing key insights into the initial activation of the UPR.

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Metadata

Authors
Spinetti, E., Ścibisz, G., Karagöz, G. E., & Covino, R.
Affiliations
  • Goethe University Frankfurt (DE)
  • University of Vienna (AT)
Corresponding author
Covino, Roberto
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2026-07-23
Volume
14
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.106716
OpenAlex
W4411056139
Cited by
0
References
2
Type
posted content
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • FWF Austrian Science Fund (10.55776/w1261, 10.55776/f79)
  • Deutsche Forschungsgemeinschaft (CRC 1507: Membrane-associated Protein Assemblies, Machineries, and Supercomplexes (P09))
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
Keywords
IRE1, unfolded protein response, endoplasmic reticulum stress, BiP, protein oligomerization, binding pocket, endoplasmic reticulum homeostasis
MeSH terms
Endoplasmic Reticulum, Membrane Glycoproteins, Models, Molecular, Peptides, Protein Binding, Protein Conformation, Saccharomyces cerevisiae, Protein Serine-Threonine Kinases, Saccharomyces cerevisiae Proteins, Molecular Dynamics Simulation, Unfolded Protein Response

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