9CBS

Crystal structure of Chaetomium thermophilum Gcn2 HisRS-like domain, catalytic domain

Summary for 9CBS

• Entry DOI: 10.2210/pdb9cbs/pdb
• Related: 9C9Q 9C9R
• Descriptor: non-specific serine/threonine protein kinase (2 entities in total)
• Functional Keywords: stress response, gcn2, trna-binding, regulatory, translation
• Biological source: Thermochaetoides thermophila
• Total number of polymer chains: 4
• Total formula weight: 150431.83

Authors

Zhang, J. (deposition date: 2024-06-20, release date: 2024-08-21, Last modification date: 2024-10-23)

Primary citation

Bou-Nader, C.,Gaikwad, S.,Bahmanjah, S.,Zhang, F.,Hinnebusch, A.G.,Zhang, J.
Gcn2 structurally mimics and functionally repurposes the HisRS enzyme for the integrated stress response.
Proc.Natl.Acad.Sci.USA, 121:e2409628121-e2409628121, 2024

PubMed Abstract: Protein kinase Gcn2 attenuates protein synthesis in response to amino acid starvation while stimulating translation of a transcriptional activator of amino acid biosynthesis. Gcn2 activation requires a domain related to histidyl-tRNA synthetase (HisRS), the enzyme that aminoacylates tRNA. While evidence suggests that deacylated tRNA binds the HisRS domain for kinase activation, ribosomal P-stalk proteins have been implicated as alternative activating ligands on stalled ribosomes. We report crystal structures of the HisRS domain of Gcn2 that reveal structural mimicry of both catalytic (CD) and anticodon-binding (ABD) domains, which in authentic HisRS bind the acceptor stem and anticodon loop of tRNA. Elements for forming histidyl adenylate and aminoacylation are lacking, suggesting that Gcn2 was repurposed for kinase activation, consistent with mutations in the CD that dysregulate yeast Gcn2 function. Substituting conserved ABD residues well positioned to contact the anticodon loop or that form a conserved ABD-CD interface impairs Gcn2 function in starved cells. Mimicry in Gcn2 of two highly conserved structural domains for binding both ends of tRNA-each crucial for Gcn2 function-supports that deacylated tRNAs activate Gcn2 and exemplifies how a metabolic enzyme is repurposed to host new local structures and sequences that confer a novel regulatory function.

PubMed: 39163341
DOI: 10.1073/pnas.2409628121

Experimental method

X-RAY DIFFRACTION (2.69 Å)