PDBsum entry: 2hz6

Signaling protein

PDB id: 2hz6

Contents

Protein chain

253 a.a. *

* Residue conservation analysis

PDB id:

2hz6

Name:

Signaling protein

Title:

The crystal structure of human ire1-alpha luminal domain

Structure:

Endoplasmic reticulum to nucleus signalling 1 isoform 1 variant. Chain: a. Fragment: n-terminal domain. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562

Biol. unit:

Dimer (from PDB file)

Resolution:

3.10Å R-factor: 0.268 R-free: 0.316

Authors:

R.J.Kaufman,Z.Xu,J.Zhou

Key ref:

J.Zhou et al. (2006). The crystal structure of human IRE1 luminal domain reveals a conserved dimerization interface required for activation of the unfolded protein response. Proc Natl Acad Sci U S A, 103, 14343-14348. PubMed id: 16973740 DOI: 10.1073/pnas.0606480103

Date:

08-Aug-06 Release date: 29-Aug-06

Protein chain

O75460  (ERN1_HUMAN) -  Serine/threonine-protein kinase/endoribonuclease IRE1

Seq: 977 a.a.

Struc: 253 a.a.*

* PDB and UniProt seqs differ at 11 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.2.7.11.1 - Non-specific serine/threonine protein kinase.
• Reaction: ATP + a protein = ADP + a phosphoprotein

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1073/pnas.0606480103

Proc Natl Acad Sci U S A 103:14343-14348 (2006)

PubMed id: 16973740

The crystal structure of human IRE1 luminal domain reveals a conserved dimerization interface required for activation of the unfolded protein response.

J.Zhou, C.Y.Liu, S.H.Back, R.L.Clark, D.Peisach, Z.Xu, R.J.Kaufman.

ABSTRACT

The unfolded protein response (UPR) is an evolutionarily conserved mechanism by which all eukaryotic cells adapt to the accumulation of unfolded proteins in the endoplasmic reticulum (ER). Inositol-requiring kinase 1 (IRE1) and PKR-related ER kinase (PERK) are two type I transmembrane ER-localized protein kinase receptors that signal the UPR through a process that involves homodimerization and autophosphorylation. To elucidate the molecular basis of the ER transmembrane signaling event, we determined the x-ray crystal structure of the luminal domain of human IRE1alpha. The monomer of the luminal domain comprises a unique fold of a triangular assembly of beta-sheet clusters. Structural analysis identified an extensive dimerization interface stabilized by hydrogen bonds and hydrophobic interactions. Dimerization creates an MHC-like groove at the interface. However, because this groove is too narrow for peptide binding and the purified luminal domain forms high-affinity dimers in vitro, peptide binding to this groove is not required for dimerization. Consistent with our structural observations, mutations that disrupt the dimerization interface produced IRE1alpha molecules that failed to either dimerize or activate the UPR upon ER stress. In addition, mutations in a structurally homologous region within PERK also prevented dimerization. Our structural, biochemical, and functional studies in vivo altogether demonstrate that IRE1 and PERK have conserved a common molecular interface necessary and sufficient for dimerization and UPR signaling.

Selected figure(s)

Figure 2.
Fig. 2. The molecular dimer structure of human IRE1 NLD. (A) Ribbon drawing of the NLD dimer looking straight down the twofold axis of symmetry. One subunit is colored as in Fig. 1B, and the other is gray. In the displayed orientation both C termini of the dimer would project into the page. (B) An enlarged view of the dimer interface after rotating the dimer in A 180° around the horizontal axis. Side chains of residues examined in our mutagenesis studies are shown as ball-and-stick models. The program Ribbons (33) was used to produce both drawings.

Figure 5.
Fig. 5. Model for staged activation of IRE1. The model depicts that several steps mediate IRE1 activation including BiP release, initial intramolecular autophosphorylation, dimerization, and dimerization-induced trans-autophosphorylation (see Discussion for details). Increasing degrees of IRE1 autophosphorylation cause higher levels of RNase activity indicated as darker shades of brown.

Figures were selected by an automated process.