2. Academic Validation
  3. Crystal Structure of the Golgi-Associated Human Nα-Acetyltransferase 60 Reveals the Molecular Determinants for Substrate-Specific Acetylation

Crystal Structure of the Golgi-Associated Human Nα-Acetyltransferase 60 Reveals the Molecular Determinants for Substrate-Specific Acetylation

  • Structure. 2016 Jul 6;24(7):1044-56. doi: 10.1016/j.str.2016.04.020.
Svein Isungset Støve 1,  Robert S Magin 2,  Håvard Foyn 3,  Bengt Erik Haug 4,  Ronen Marmorstein 5,  Thomas Arnesen 6
Affiliations

Affiliations

  • 1 Department of Molecular Biology, University of Bergen, 5020 Bergen, Norway; Department of Surgery, Haukeland University Hospital, 5021 Bergen, Norway.
  • 2 Department of Biochemistry and Biophysics, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Graduate Group in Biochemistry and Molecular Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Program in Gene Expression and Regulation, Wistar Institute, Philadelphia, PA 19104, USA.
  • 3 Department of Molecular Biology, University of Bergen, 5020 Bergen, Norway.
  • 4 Department of Chemistry, University of Bergen, 5020 Bergen, Norway.
  • 5 Department of Biochemistry and Biophysics, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Graduate Group in Biochemistry and Molecular Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Program in Gene Expression and Regulation, Wistar Institute, Philadelphia, PA 19104, USA. Electronic address: [email protected].
  • 6 Department of Molecular Biology, University of Bergen, 5020 Bergen, Norway; Department of Surgery, Haukeland University Hospital, 5021 Bergen, Norway. Electronic address: [email protected].
PMID: 27320834 DOI: 10.1016/j.str.2016.04.020
Abstract

N-Terminal acetylation is a common and important protein modification catalyzed by N-terminal acetyltransferases (NATs). Six human NATs (NatA-NatF) contain one catalytic subunit each, Naa10 to Naa60, respectively. In contrast to the ribosome-associated NatA to NatE, NatF/Naa60 specifically associates with Golgi membranes and acetylates transmembrane proteins. To gain insight into the molecular basis for the function of Naa60, we developed an Naa60 bisubstrate CoA-peptide conjugate inhibitor, determined its X-ray structure when bound to CoA and inhibitor, and carried out biochemical experiments. We show that Naa60 adapts an overall fold similar to that of the catalytic subunits of ribosome-associated NATs, but with the addition of two novel elongated loops that play important roles in substrate-specific binding. One of these loops mediates a dimer to monomer transition upon substrate-specific binding. Naa60 employs a catalytic mechanism most similar to Naa50. Collectively, these data reveal the molecular basis for Naa60-specific acetyltransferase activity with implications for its Golgi-specific functions.

Keywords

N-terminal acetylation; NAT; Naa60; NatF; acetyltransferase; crystal structure.

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