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The role of phosphorylation of Ire1 in its activation loop in regulation of its RNase activity

ARMSTRONG, MICHAEL,CRAIG (2016) The role of phosphorylation of Ire1 in its activation loop in regulation of its RNase activity. Masters thesis, Durham University.

PDF (Masters of Science by Research Thesis - M Armstrong) - Accepted Version


Ire1 is a protein kinase endoribonuclease (RNase) and a resident protein of the endoplasmic reticulum (ER) of Saccharomyces cerevisiae and a homologue to the Ire1a ER protein found in humans. Ire1 activates splicing of the mRNA of the unfolded protein response (UPR) gene HAC1. This splicing is a response to the accumulation of unfolded or misfolded proteins in the ER lumen. Splicing of HAC1 mRNA results in the translation of the Hac1 protein Hac1i which contains a bZIP transcription factor which promotes the expression of UPR-associated genes which ultimately leads to the alleviation of ER stress. The activation of Ire1 was previously thought to be dependent on phosphorylation within the Ire1 activation loop (a-loop). Here it is shown that in “phospho-dead” mutants, some level of splicing and UPR-activity is retained and that the aspartic acid residue (D836) within the a-loop allows for this retention. Furthermore, it was confirmed that mutation of D836 to alanine completely eliminates HAC1 mRNA splicing. This work suggests that phosphorylation of the a-loop is critical but not essential to RNase activation and the UPR.

Item Type:Thesis (Masters)
Award:Master of Science
Keywords:Ire1, Endoplasmic Reticulum, Unfolded Protein Response, Protein Kinase, Phosphorylation, Stress Response, Activation loop
Faculty and Department:Faculty of Science > Biological and Biomedical Sciences, School of
Thesis Date:2016
Copyright:Copyright of this thesis is held by the author
Deposited On:17 Mar 2017 12:15

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