Deciphering the molecular mechanisms of Yih1/IMPACT : identification of important Yih1 amino acids for inhibition of the general amino acid control response : a thesis presented in partial fulfilment of the requirements for the degree of Master of Science in Biological Science at Massey University, Albany, New Zealand. EMBARGOED until 29/01/2025.
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2022
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Massey University
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Abstract
It is crucial that eukaryotes adjust their cellular gene expression profile in response to dynamic cellular changes. Failure to do this can be detrimental to the cell. Gcn2 is a protein kinase that is central to a signalling pathway that decreases general protein synthesis and increases transcription of specific stress response genes in response to amino acid starvation in eukaryotes. Gcn2 needs to be tightly regulated to maintain cellular homeostasis. Gcn2 needs to directly bind Gcn1 to be activated. Yeast IMPACT homolog 1 (Yih1), or IMPACT (Mammals), is an inhibitor of Gcn2. It does this by competing with Gcn2 for Gcn1 binding. However, Yih1 only inhibits Gcn2 under certain circumstances. This implies that Yih1 itself must be regulated. Furthermore, this means that Yih1 resides in the cell in an inactive form or an active form that is primed for Gcn2 inhibition. The precise interactions between Yih1 and Gcn1 are not known yet, nor is it known how intramolecular interactions determine when Yih1 is active or inactive. Given the importance of IMPACT in neuronal development, it is crucial to understand the molecular mechanisms of Yih1/IMPACT-mediated Gcn2 inhibition. In this research, I aimed to identify relevant Yih1 amino acids that are involved in Gcn2 inhibition, using Baker’s yeast (S. cerevisiae) as a model organism. At present, the only known important amino acids for Yih1 function are D102 and E106 together. I have utilised and established a yeast system that enabled us to score the ability of Yih1 to inhibit Gcn2 . . . This research helps to provide more insight into the regulation of Gcn2 by Yih1/IMPACT and brings us a step closer to understanding diseases associated with Gcn2 dysregulation, like Alzheimer’s disease.
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Embargoed until 29/01/2025