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Title: Structure and Mechanism of Acetylation by the N-Terminal Dual Enzyme NatA/Naa50 Complex

Journal Article · · Structure
 [1];  [2];  [1];  [1];  [1];  [1]
  1. Univ. of Pennsylvania, Philadelphia, PA (United States)
  2. Dana-Farber Cancer Inst., Boston, MA (United States)
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NatA co-translationally acetylates the N termini of over 40% of eukaryotic proteins and can associate with another catalytic subunit, Naa50, to form a ternary NatA/Naa50 dual enzyme complex (also called NatE). The molecular basis of association between Naa50 and NatA and the mechanism for how their association affects their catalytic activities in yeast and human are poorly understood. Here, we determined the X-ray crystal structure of yeast NatA/Naa50 as a scaffold to understand coregulation of NatA/Naa50 activity in both yeast and human. We find that Naa50 makes evolutionarily conserved contacts to both the Naa10 and Naa15 subunits of NatA. These interactions promote catalytic crosstalk within the human complex, but do so to a lesser extent in the yeast complex, where Naa50 activity is compromised. These studies have implications for understanding the role of the NatA/Naa50 complex in modulating the majority of the N-terminal acetylome in diverse species.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE; National Science Foundation (NSF); National Institutes of Health (NIH
OSTI ID:
1569889
Journal Information:
Structure, Journal Name: Structure Journal Issue: 7 Vol. 27; ISSN 0969-2126
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

References (68)

hNaa10p contributes to tumorigenesis by facilitating DNMT1-mediated tumor suppressor gene silencing journal August 2010
Structure of a Ternary Naa50p (NAT5/SAN) N-terminal Acetyltransferase Complex Reveals the Molecular Basis for Substrate-specific Acetylation journal September 2011
Crystal Structure of the Golgi-Associated Human Nα-Acetyltransferase 60 Reveals the Molecular Determinants for Substrate-Specific Acetylation journal July 2016
Yeast Nα-terminal acetyltransferases are associated with ribosomes journal January 2008
N-terminal acetylome analysis reveals the specificity of Naa50 (Nat5) and suggests a kinetic competition between N-terminal acetyltransferases and methionine aminopeptidases journal June 2015
Composition and function of the eukaryotic N-terminal acetyltransferase subunits journal August 2003
Nα-acetylated Sir3 stabilizes the conformation of a nucleosome-binding loop in the BAH domain journal August 2013
N-α-Acetyltransferase 10 Protein Suppresses Cancer Cell Metastasis by Binding PIX Proteins and Inhibiting Cdc42/Rac1 Activity journal February 2011
[20] Processing of X-ray diffraction data collected in oscillation mode book January 1997
Opposing Functions of the N-terminal Acetyltransferases Naa50 and NatA in Sister-chromatid Cohesion journal September 2016
Control of Protein Quality and Stoichiometries by N-Terminal Acetylation and the N-End Rule Pathway journal May 2013
Molecular determinants of the N-terminal acetyltransferase Naa60 anchoring to the Golgi membrane journal February 2017
Fast, scalable generation of high‐quality protein multiple sequence alignments using Clustal Omega journal January 2011
First Things First: Vital Protein Marks by N-Terminal Acetyltransferases journal September 2016
Naa50/San-dependent N-terminal acetylation of Scc1 is potentially important for sister chromatid cohesion journal December 2016
PHENIX: a comprehensive Python-based system for macromolecular structure solution journal January 2010
Identification of the human Nα-acetyltransferase complex B (hNatB): a complex important for cell-cycle progression journal September 2008
The Chaperone-Like Protein HYPK Acts Together with NatA in Cotranslational N-Terminal Acetylation and Prevention of Huntingtin Aggregation journal April 2010
NatF Contributes to an Evolutionary Shift in Protein N-Terminal Acetylation and Is Important for Normal Chromosome Segregation journal July 2011
A Role for Human N-alpha Acetyltransferase 30 (Naa30) in Maintaining Mitochondrial Integrity journal November 2016
Absence of N-terminal acetyltransferase diversification during evolution of eukaryotic organisms journal February 2016
A genome-wide RNAi screen reveals multiple regulators of caspase activation journal November 2007
Depletion of histone N-terminal-acetyltransferase Naa40 induces p53-independent apoptosis in colorectal cancer cells via the mitochondrial pathway journal December 2015
N-Terminal Acetylation of Cellular Proteins Creates Specific Degradation Signals journal January 2010
N-terminal Acetylation Stabilizes N-terminal Helicity in Lipid- and Micelle-bound α-Synuclein and Increases Its Affinity for Physiological Membranes journal February 2014
The biological functions of Naa10 — From amino-terminal acetylation to human disease journal August 2015
Loss of amino-terminal acetylation suppresses a prion phenotype by modulating global protein folding journal July 2014
An N α -Acetyltransferase Responsible for Acetylation of the N-terminal Residues of Histones H4 and H2A journal August 2003
Molecular Basis of Substrate Specific Acetylation by N-Terminal Acetyltransferase NatB journal April 2017
Identification and characterization of the human ARD1–NATH protein acetyltransferase complex journal March 2005
Probing the interaction between NatA and the ribosome for co-translational protein acetylation journal October 2017
The acetyltransferase activity of San stabilizes the mitotic cohesin at the centromeres in a shugoshin-independent manner journal May 2007
Two Putative Acetyltransferases, San and Deco, Are Required for Establishing Sister Chromatid Cohesion in Drosophila journal December 2003
Knockdown of Human N -Terminal Acetyltransferase Complex C Leads to p53-Dependent Apoptosis and Aberrant Human Arl8b Localization journal April 2009
Structural basis of HypK regulating N-terminal acetylation by the NatA complex journal June 2017
Protein N-terminal acetyltransferases: when the start matters journal April 2012
Structure of Human NatA and Its Regulation by the Huntingtin Interacting Protein HYPK journal July 2018
N-alpha-terminal Acetylation of Histone H4 Regulates Arginine Methylation and Ribosomal DNA Silencing journal September 2013
Molecular identification and functional characterization of the first Nα-acetyltransferase in plastids by global acetylome profiling journal June 2015
Regulation and Destabilization of HIF-1α by ARD1-Mediated Acetylation journal November 2002
The Yeast Nα-Acetyltransferase NatA Is Quantitatively Anchored to the Ribosome and Interacts with Nascent Polypeptides journal October 2003
Golgi targeting of ARF-like GTPase Arl3p requires its Nα-acetylation and the integral membrane protein Sys1p journal April 2004
Proteomics analyses reveal the evolutionary conservation and divergence of N-terminal acetyltransferases from yeast and humans journal May 2009
Correlation of Expression of Human Arrest-Defective-1 (hARD1) Protein With Breast Cancer journal November 2009
NAA10 controls osteoblast differentiation and bone formation as a feedback regulator of Runx2 journal November 2014
N-Terminal Acetylation Acts as an Avidity Enhancer Within an Interconnected Multiprotein Complex journal September 2011
Coot model-building tools for molecular graphics journal November 2004
Structural determinants and cellular environment define processed actin as the sole substrate of the N-terminal acetyltransferase NAA80 journal March 2018
NAA80 is actin’s N-terminal acetyltransferase and regulates cytoskeleton assembly and cell motility journal March 2018
Induction of apoptosis in human cells by RNAi-mediated knockdown of hARD1 and NATH, components of the protein N-α-acetyltransferase complex journal March 2006
Deciphering key features in protein structures with the new ENDscript server journal April 2014
Toward the structural genomics of complexes: Crystal structure of a PE/PPE protein complex from Mycobacterium tuberculosis journal May 2006
Molecular basis for N-terminal acetylation by the heterodimeric NatA complex journal August 2013
NATH, a novel gene overexpressed in papillary thyroid carcinomas journal July 2002
A novel acetylation of β-tubulin by San modulates microtubule polymerization via down-regulating tubulin incorporation journal February 2011
IP6 (Inositol Hexaphosphate) as a Signaling Molecule journal August 2012
Proteome-derived Peptide Libraries Allow Detailed Analysis of the Substrate Specificities of N α -acetyltransferases and Point to hNaa10p as the Post-translational Actin N α -acetyltransferase journal March 2011
Implication of human N-α-acetyltransferase 5 in cellular proliferation and carcinogenesis journal September 2008
Human Naa50p (Nat5/San) Displays Both Protein N α - and N ϵ -Acetyltransferase Activity journal September 2009
Yeast MAK3 N-acetyltransferase recognizes the N-terminal four amino acids of the major coat protein (gag) of the L-A double-stranded RNA virus journal May 1993
Using VAAST to Identify an X-Linked Disorder Resulting in Lethality in Male Infants Due to N-Terminal Acetyltransferase Deficiency journal July 2011
Targeting of the Arf-like GTPase Arl3p to the Golgi requires N-terminal acetylation and the membrane protein Sys1p journal April 2004
Ribosome–NatA architecture reveals that rRNA expansion segments coordinate N-terminal acetylation journal December 2018
Naa10 in development and disease journal September 2015
N-terminal protein modifications: Bringing back into play the ribosome journal July 2015
The Molecular Basis for Histone H4- and H2A-Specific Amino-Terminal Acetylation by NatD journal February 2015
An Organellar Nα-Acetyltransferase, Naa60, Acetylates Cytosolic N Termini of Transmembrane Proteins and Maintains Golgi Integrity journal March 2015
Protein N-terminal acetyltransferases in cancer journal March 2012

Cited By (1)

Molecular basis for N-terminal acetylation by human NatE and its modulation by HYPK journal February 2020

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Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
N-terminal acetylation
x-ray crystallography
protein complex
NatA
Naa50
NatE