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Structural basis for unfolded protein recognition by the ER stress-sensor IRE1alpha

ABSTRACT: ERN1/IRE1alpha is an endoplasmic reticulum sensor that recognizes misfolded proteins to activate the unfolded protein response. We used cholera toxin (CTx), which activates IRE1alpha in cells, to understand how this occurs. In vitro, the A1 subunit of CTx (CTxA1) bound the IRE1alpha lumenal domain (IRE1alphaLD). Global unfolding was not required. Instead, IRE1alphaLD recognized a 7-residue motif within a metastable region of CTxA1 that was also found in other microbial and host proteins involved in IRE1alpha activation. Binding mapped to a pocket on IRE1alphaLD normally occupied by a segment of the C-terminal flexible loop implicated in IRE1alpha regulation. Mutation of the recognition motif blocked CTx-induced IRE1alpha activation in live cells. These findings describe a mechanism for substrate recognition by IRE1alpha that induces the unfolded protein response.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Steven A. Carr

PROVIDER: MSV000091745 | MassIVE | Wed Apr 19 10:17:00 BST 2023

REPOSITORIES: MassIVE

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