HYPK promotes N-terminal protein acetylation through rapid ribosome exchange of NatA
Year: 2025
Type: article
Abstract: Numerous protein biogenesis factors cotranslationally facilitate the maturation of nascent proteins. Among them, N-terminal acetyltransferase A (NatA) acetylates the N terminus of ∼40% of the eukaryotic proteome. NatA is bound to Huntingtin-interacting protein K (HYPK), which inhibits NatA activity in vitro but enhances function in vivo. Here, kinetic and in-cell measurements resolve this paradox, showing that HYPK acts as a ribosome exchange factor for NatA. Without HYPK, hyper-tight ribosome binding prevents NatA from accessing additional ribosomes following each round of acetylation. HYPK accelerates NatA dissociation from the ribosome to license multiple turnovers, allowing a sub-stoichiometric level of this enzyme to globally acetylate the nascent proteome. Our results uncover a previously unidentified function of HYPK and demonstrate that a "Goldilocks" zone of ribosome interaction kinetics is required for cotranslational protein biogenesis machineries to act on all translating ribosomes in the cell.
Source: Molecular Cell
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $10,400
Funders: Rajiv Gandhi Centre for Biotechnology, Department of Biotechnology, Ministry of Science and Technology, India, Howard Hughes Medical Institute, Department of Biotechnology, Ministry of Science and Technology, India, National Institutes of Health, Whiting School of Engineering, Johns Hopkins University, Science and Engineering Research Board, National Institute of General Medical Sciences
OpenAlex ID: W4417198418