Interaction between the tRNA-Binding and C-Terminal Domains of Yeast Gcn2 Regulates Kinase Activity In Vivo

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dc.contributor.author Lageix, S.
dc.contributor.author Zhang, J. W.
dc.contributor.author Rothenburg, Stefan
dc.contributor.author Hinnebusch, A. G.
dc.date.accessioned 2016-04-04T22:13:52Z
dc.date.available 2016-04-04T22:13:52Z
dc.identifier.uri http://hdl.handle.net/2097/32246
dc.description Citation: Lageix, S., Zhang, J. W., Rothenburg, S., & Hinnebusch, A. G. (2015). Interaction between the tRNA-Binding and C-Terminal Domains of Yeast Gcn2 Regulates Kinase Activity In Vivo. Plos Genetics, 11(2), 28. doi:10.1371/journal.pgen.1004991
dc.description The stress-activated protein kinase Gcn2 regulates protein synthesis by phosphorylation of translation initiation factor eIF2 alpha. Gcn2 is activated in amino acid-deprived cells by binding of uncharged tRNA to the regulatory domain related to histidyl-tRNA synthetase, but the molecular mechanism of activation is unclear. We used a genetic approach to identify a key regulatory surface in Gcn2 that is proximal to the predicted active site of the HisRS domain and likely remodeled by tRNA binding. Mutations leading to amino acid substitutions on this surface were identified that activate Gcn2 at low levels of tRNA binding (Gcd(-) phenotype), while other substitutions block kinase activation (Gcn(-) phenotype), in some cases without altering tRNA binding by Gcn2 in vitro. Remarkably, the Gcn(-) substitutions increase affinity of the HisRS domain for the C-terminal domain (CTD), previously implicated as a kinase autoinhibitory segment, in a manner dampened by HisRS domain Gcd(-) substitutions and by amino acid starvation in vivo. Moreover, tRNA specifically antagonizes HisRS/CTD association in vitro. These findings support a model wherein HisRS-CTD interaction facilitates the autoinhibitory function of the CTD in nonstarvation conditions, with tRNA binding eliciting kinase activation by weakening HisRS-CTD association with attendant disruption of the autoinhibitory KD-CTD interaction.
dc.relation.uri https://doi.org/10.1371/journal.pgen.1004991
dc.rights CC0 1.0 Universal (CC0 1.0)
dc.rights.uri https://creativecommons.org/publicdomain/zero/1.0/
dc.subject Uncharged Transfer-Rna
dc.subject Acid-Starved Cells
dc.subject Protein-Kinase
dc.subject Amino-Acid
dc.subject Translation Initiation
dc.subject Saccharomyces-Cerevisiae
dc.title Interaction between the tRNA-Binding and C-Terminal Domains of Yeast Gcn2 Regulates Kinase Activity In Vivo
dc.type Article
dc.date.published 2015
dc.citation.doi 10.1371/journal.pgen.1004991
dc.citation.issn 1553-7390
dc.citation.issue 2
dc.citation.jtitle PLoS Genetics
dc.citation.spage 28
dc.citation.volume 11
dc.contributor.authoreid sr1hsv


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