Structure of a ternary Naa50p (NAT5/SAN) N-terminal acetyltransferase complex reveals the molecular basis for substrate-specific acetylation

Glen Liszczak, Thomas Arnesen, Ronen Marmorsteins

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

The co-translational modification of N-terminal acetylation is ubiquitous among eukaryotes and has been reported to have a wide range of biological effects. The human N-terminal acetyl-transferase (NAT) Naa50p (NAT5/SAN) acetylates the α-amino group of proteins containing an N-terminal methionine residue and is essential for proper sister chromatid cohesion and chromosome condensation. The elevated activity of NATs has also been correlated with cancer, making these enzymes attractive therapeutic targets. We report the x-ray crystal structure of Naa50p bound to a native substrate peptide fragment and CoA. Wefound that the peptide backbone of the substrate is anchored to the protein through a series of backbone hydrogen bonds with the first methionine residue specified through multiple van der Waals contacts, together creating an α-amino methionine-specific pocket. We also employed structure-based mutagenesis; the results support the importance of the α-amino methionine-specific pocket of Naa50p and are consistent with the proposal that conserved histidine and tyrosine residues play important catalytic roles. Superposition of the ternary Naa50p complex with the peptide-bound Gcn5 histone acetyltransferase revealed that the two enzymes share a Gcn5-related N-acetyltransferase fold but differ in their respective substrate-binding grooves such that Naa50p can accommodate only an α-amino substrate and not a side chain lysine substrate that is acetylated by lysine acetyltransferase enzymes such as Gcn5. The structure of the ternary Naa50p complex also provides the first molecular scaffold for the design of NAT-specific small molecule inhibitors with possible therapeutic applications.

Original languageEnglish (US)
Pages (from-to)37002-37010
Number of pages9
JournalJournal of Biological Chemistry
Volume286
Issue number42
DOIs
StatePublished - Oct 21 2011
Externally publishedYes

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N-Terminal Acetyltransferases
Acetylation
Methionine
Substrates
Transferases
Acetyltransferases
Enzymes
Lysine
Histone Acetyltransferases
Peptides
Peptide Fragments
Chromatids
Coenzyme A
Eukaryota
Mutagenesis
Histidine
Tyrosine
Hydrogen
Chromosomes
Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Structure of a ternary Naa50p (NAT5/SAN) N-terminal acetyltransferase complex reveals the molecular basis for substrate-specific acetylation. / Liszczak, Glen; Arnesen, Thomas; Marmorsteins, Ronen.

In: Journal of Biological Chemistry, Vol. 286, No. 42, 21.10.2011, p. 37002-37010.

Research output: Contribution to journalArticle

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