https://www.nature.com/articles/nature07661
The unfolded protein response signals through high-order assembly of Ire1
Nature volume 457, pages 687–693 (05 February 2009) |
Aberrant
folding of proteins in the endoplasmic reticulum activates the
bifunctional transmembrane kinase/endoribonuclease Ire1.
Ire1 excises an intron from HAC1 messenger RNA in yeasts and Xbp1 messenger RNA in metozoans encoding homologous transcription factors.
This non-conventional mRNA splicing event initiates the unfolded protein response, a transcriptional program that relieves the endoplasmic reticulum stress.
Here we show that oligomerization is central to Ire1 function and is an intrinsic attribute of its cytosolic domains. We obtained the 3.2-Å crystal structure of the oligomer of the Ire1 cytosolic domains in complex with a kinase inhibitor that acts as a potent activator of the Ire1 RNase. The structure reveals a rod-shaped assembly that has no known precedence among kinases. This assembly positions the kinase domain for trans-autophosphorylation, orders the RNase domain, and creates an interaction surface for binding of the mRNA substrate. Activation of Ire1 through oligomerization expands the mechanistic repertoire of kinase-based signalling receptors.
2011
https://www.ncbi.nlm.nih.gov/pubmed/22116877
Kertomus PERKi kehittelystä jatkuu...https://researchspace.auckland.ac.nz/handle/2292/34511
Ire1 excises an intron from HAC1 messenger RNA in yeasts and Xbp1 messenger RNA in metozoans encoding homologous transcription factors.
This non-conventional mRNA splicing event initiates the unfolded protein response, a transcriptional program that relieves the endoplasmic reticulum stress.
Here we show that oligomerization is central to Ire1 function and is an intrinsic attribute of its cytosolic domains. We obtained the 3.2-Å crystal structure of the oligomer of the Ire1 cytosolic domains in complex with a kinase inhibitor that acts as a potent activator of the Ire1 RNase. The structure reveals a rod-shaped assembly that has no known precedence among kinases. This assembly positions the kinase domain for trans-autophosphorylation, orders the RNase domain, and creates an interaction surface for binding of the mRNA substrate. Activation of Ire1 through oligomerization expands the mechanistic repertoire of kinase-based signalling receptors.
2011
https://www.ncbi.nlm.nih.gov/pubmed/22116877
Abstract
The vast majority
of proteins that a cell secretes or displays on its surface first enter
the endoplasmic reticulum (ER), where they fold and assemble. Only
properly assembled proteins advance from the ER to the cell surface. To
ascertain fidelity in protein folding, cells regulate the
protein-folding capacity in the ER according to need.
The ER responds to the burden of unfolded proteins proteins in its lumen (ER stress) by activating intracellular signal transduction pathways, collectively termed the unfolded protein response (UPR).
Together, at least three mechanistically distinct branches of the UPR regulate the expression of numerous genes that maintain homeostasis in the ER or induce apoptosis if ER stress remains unmitigated.
Recent advances shed light on mechanistic complexities and on the role of the UPR in numerous diseases.
You Tube 2015 ASEMB Plenary lecture. From protein folding to cognition The Serendipitous discovery.
https://www.youtube.com/watch?v=AJjOvzIdxqA
The ER responds to the burden of unfolded proteins proteins in its lumen (ER stress) by activating intracellular signal transduction pathways, collectively termed the unfolded protein response (UPR).
Together, at least three mechanistically distinct branches of the UPR regulate the expression of numerous genes that maintain homeostasis in the ER or induce apoptosis if ER stress remains unmitigated.
Recent advances shed light on mechanistic complexities and on the role of the UPR in numerous diseases.
You Tube 2015 ASEMB Plenary lecture. From protein folding to cognition The Serendipitous discovery.
https://www.youtube.com/watch?v=AJjOvzIdxqA
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