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Ire1 protein; serine/threonine protein kinase/endoribonuclease IRE1; inositol-requiring 1; hIRE1p; IRE1a; Ire1-alpha; endoplasmic reticulum-to-nucleus signaling 1 (IRE1, ERN1)
Function:
- a sensor for the accumulation of unfolded proteins in the endoplasmic reticulum (ER)
- Ire1 initiates the unfolded protein response pathway, triggering growth arrest & apoptosis
- senses unfolded proteins in the lumen of the ER via its N-terminal domain which leads to enzyme auto-activation
- the active endoribonuclease domain splices XBP1 mRNA to generate a new C-terminus, converting it into a potent unfolded-protein response transcriptional activator & triggering growth arrest & apoptosis
- Ire1 may be a substrate of aspartyl protease activity of presenilins
- binds HSPA5, a negative regulator of the unfolded protein response; bindin may disrupt homodimerization & prevent activation of ERN1
- autophosphorylated
Structure:
- homodimer; disulfide-linked
- dimer formation is driven by hydrophobic interactions within the N-terminal luminal domains & stabilized by disulfide bridges.
- belongs to the protein kinase superfamily, Ser/Thr protein kinase family
- contains 1 KEN domain
- contains 1 protein kinase domain; kinase domain is activated by trans-autophosphorylation kinase activity is required for activation of the endoribonuclease domain
Cofactor: Mg+2
Compartment: endoplasmic reticulum membrane
Alternative splicing: named isoforms=2
Expression:
- ubiquitously expressed
- high levels observed in pancreatic tissue
General
endoribonuclease
glycoprotein
membrane protein
serine/threonine kinase
Properties
SIZE: MW = 110 kD
entity length = 977 aa
COMPARTMENT: cellular membrane
MOTIF: signal sequence {1-18}
N-glycosylation site {N176}
transmembrane domain {444-464}
kinase domain
SITE: 571-832
MOTIF: ATP-binding site
NAME: ATP-binding site
SITE: 577-585
ATP-binding site
NAME: ATP-binding site
SITE: 599-599
aspartate residue {D688}
Ribonuclease {837-963}
STATE: active state
Database Correlations
OMIM 604033
UniProt O75460
PFAM correlations
Entrez Gene 2081
Kegg hsa:2081
ENZYME 2.7.11.1
References
- Selkoe DJ.
Alzheimer's disease: genes, proteins, and therapy.
Physiol Rev. 2001 Apr;81(2):741-66. Review.
PMID: 11274343
- UniProt :accession O75460