Structural basis of HypK regulating N-terminal acetylation by the NatA complex

Nat Commun. 2017 Jun 6;8:15726. doi: 10.1038/ncomms15726.

Abstract

In eukaryotes, N-terminal acetylation is one of the most common protein modifications involved in a wide range of biological processes. Most N-acetyltransferase complexes (NATs) act co-translationally, with the heterodimeric NatA complex modifying the majority of substrate proteins. Here we show that the Huntingtin yeast two-hybrid protein K (HypK) binds tightly to the NatA complex comprising the auxiliary subunit Naa15 and the catalytic subunit Naa10. The crystal structures of NatA bound to HypK or to a N-terminal deletion variant of HypK were determined without or with a bi-substrate analogue, respectively. The HypK C-terminal region is responsible for high-affinity interaction with the C-terminal part of Naa15. In combination with acetylation assays, the HypK N-terminal region is identified as a negative regulator of the NatA acetylation activity. Our study provides mechanistic insights into the regulation of this pivotal protein modification.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Acetyltransferases / genetics
  • Carrier Proteins / chemistry*
  • Catalytic Domain
  • Chaetomium
  • Crystallography, X-Ray
  • Humans
  • Light
  • Models, Molecular
  • N-Terminal Acetyltransferase A / chemistry*
  • Peptides / chemistry
  • Protein Binding
  • Protein Biosynthesis
  • Protein Denaturation
  • Protein Domains
  • Protein Multimerization
  • Protein Processing, Post-Translational
  • Protein Structure, Secondary
  • Scattering, Radiation
  • Selenomethionine / chemistry

Substances

  • Carrier Proteins
  • HYPK protein, human
  • Peptides
  • Selenomethionine
  • Acetyltransferases
  • N-Terminal Acetyltransferase A