Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 327 (5968): 973-977

Copyright © 2010 by the American Association for the Advancement of Science

N-Terminal Acetylation of Cellular Proteins Creates Specific Degradation Signals

Cheol-Sang Hwang, Anna Shemorry, Alexander Varshavsky*

Abstract: The retained N-terminal methionine (Met) residue of a nascent protein is often N-terminally acetylated (Nt-acetylated). Removal of N-terminal Met by Met-aminopeptidases frequently leads to Nt-acetylation of the resulting N-terminal alanine (Ala), valine (Val), serine (Ser), threonine (Thr), and cysteine (Cys) residues. Although a majority of eukaryotic proteins (for example, more than 80% of human proteins) are cotranslationally Nt-acetylated, the function of this extensively studied modification is largely unknown. Using the yeast Saccharomyces cerevisiae, we found that the Nt-acetylated Met residue could act as a degradation signal (degron), targeted by the Doa10 ubiquitin ligase. Moreover, Doa10 also recognized the Nt-acetylated Ala, Val, Ser, Thr, and Cys residues. Several examined proteins of diverse functions contained these N-terminal degrons, termed AcN-degrons, which are a prevalent class of degradation signals in cellular proteins.

Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.

* To whom correspondence should be addressed. E-mail: avarsh{at}

Identification of a Key Lysine Residue in Heat Shock Protein 90 Required for Azole and Echinocandin Resistance in Aspergillus fumigatus.
F. Lamoth, P. R. Juvvadi, E. J. Soderblom, M. A. Moseley, Y. G. Asfaw, and W. J. Steinbach (2014)
Antimicrob. Agents Chemother. 58, 1889-1896
   Abstract »    Full Text »    PDF »
Calpain-generated natural protein fragments as short-lived substrates of the N-end rule pathway.
K. I. Piatkov, J.-H. Oh, Y. Liu, and A. Varshavsky (2014)
PNAS 111, E817-E826
   Abstract »    Full Text »    PDF »
N-terminal Acetylation Stabilizes N-terminal Helicity in Lipid- and Micelle-bound {alpha}-Synuclein and Increases Its Affinity for Physiological Membranes.
I. Dikiy and D. Eliezer (2014)
J. Biol. Chem. 289, 3652-3665
   Abstract »    Full Text »    PDF »
Bridging the gap between transcriptome and proteome measurements identifies post-translationally regulated genes.
Y. Gunawardana and M. Niranjan (2013)
Bioinformatics 29, 3060-3066
   Abstract »    Full Text »    PDF »
High-throughput Analysis of in vivo Protein Stability.
I. Kim, C. R. Miller, D. L. Young, and S. Fields (2013)
Mol. Cell. Proteomics 12, 3370-3378
   Abstract »    Full Text »    PDF »
Proteome-Wide Measurement of Protein Half-Lives and Translation Rates in Vasopressin-Sensitive Collecting Duct Cells.
P. C. Sandoval, D. H. Slentz, T. Pisitkun, F. Saeed, J. D. Hoffert, and M. A. Knepper (2013)
J. Am. Soc. Nephrol. 24, 1793-1805
   Abstract »    Full Text »    PDF »
Previously unknown role for the ubiquitin ligase Ubr1 in endoplasmic reticulum-associated protein degradation.
A. Stolz, S. Besser, H. Hottmann, and D. H. Wolf (2013)
PNAS 110, 15271-15276
   Abstract »    Full Text »    PDF »
Implications for the evolution of eukaryotic amino-terminal acetyltransferase (NAT) enzymes from the structure of an archaeal ortholog.
G. Liszczak and R. Marmorstein (2013)
PNAS 110, 14652-14657
   Abstract »    Full Text »    PDF »
N-terminal acetylation of the yeast Derlin Der1 is essential for Hrd1 ubiquitin-ligase activity toward luminal ER substrates.
D. Zattas, D. J. Adle, E. M. Rubenstein, and M. Hochstrasser (2013)
Mol. Biol. Cell 24, 890-900
   Abstract »    Full Text »    PDF »
UBR box N-recognin-4 (UBR4), an N-recognin of the N-end rule pathway, and its role in yolk sac vascular development and autophagy.
T. Tasaki, S. T. Kim, A. Zakrzewska, B. E. Lee, M. J. Kang, Y. D. Yoo, H. J. Cha-Molstad, J. Hwang, N. K. Soung, K. S. Sung, et al. (2013)
PNAS 110, 3800-3805
   Abstract »    Full Text »    PDF »
The DegraBase: A Database of Proteolysis in Healthy and Apoptotic Human Cells.
E. D. Crawford, J. E. Seaman, N. Agard, G. W. Hsu, O. Julien, S. Mahrus, H. Nguyen, K. Shimbo, H. A. I. Yoshihara, M. Zhuang, et al. (2013)
Mol. Cell. Proteomics 12, 813-824
   Abstract »    Full Text »    PDF »
Linking Post-Translational Modifications and Variation of Phenotypic Traits.
W. Albertin, P. Marullo, M. Bely, M. Aigle, A. Bourgais, O. Langella, T. Balliau, D. Chevret, B. Valot, T. da Silva, et al. (2013)
Mol. Cell. Proteomics 12, 720-735
   Abstract »    Full Text »    PDF »
Cdc48/p97 promotes degradation of aberrant nascent polypeptides bound to the ribosome.
R. Verma, R. S. Oania, N. J. Kolawa, and R. J. Deshaies (2013)
eLife Sci 2, e00308
   Abstract »    Full Text »    PDF »
Protein N-terminal Acetyltransferases Act as N-terminal Propionyltransferases In Vitro and In Vivo.
H. Foyn, P. Van Damme, S. I. Stove, N. Glomnes, R. Evjenth, K. Gevaert, and T. Arnesen (2013)
Mol. Cell. Proteomics 12, 42-54
   Abstract »    Full Text »    PDF »
N-terminal Protein Processing: A Comparative Proteogenomic Analysis.
S. Bonissone, N. Gupta, M. Romine, R. A. Bradshaw, and P. A. Pevzner (2013)
Mol. Cell. Proteomics 12, 14-28
   Abstract »    Full Text »    PDF »
A Dominant Point Mutation in a RINGv E3 Ubiquitin Ligase Homoeologous Gene Leads to Cleistogamy in Brassica napus.
Y.-H. Lu, D. Arnaud, H. Belcram, C. Falentin, P. Rouault, N. Piel, M.-O. Lucas, J. Just, M. Renard, R. Delourme, et al. (2012)
PLANT CELL 24, 4875-4891
   Abstract »    Full Text »    PDF »
Plastid Proteostasis and Heterologous Protein Accumulation in Transplastomic Plants.
F. De Marchis, A. Pompa, and M. Bellucci (2012)
Plant Physiology 160, 571-581
   Full Text »    PDF »
N-terminal acetylome analyses and functional insights of the N-terminal acetyltransferase NatB.
P. Van Damme, M. Lasa, B. Polevoda, C. Gazquez, A. Elosegui-Artola, D. S. Kim, E. De Juan-Pardo, K. Demeyer, K. Hole, E. Larrea, et al. (2012)
PNAS 109, 12449-12454
   Abstract »    Full Text »    PDF »
The N-end rule pathway counteracts cell death by destroying proapoptotic protein fragments.
K. I. Piatkov, C. S. Brower, and A. Varshavsky (2012)
PNAS 109, E1839-E1847
   Abstract »    Full Text »    PDF »
Comparative Large Scale Characterization of Plant versus Mammal Proteins Reveals Similar and Idiosyncratic N-{alpha}-Acetylation Features.
W. V. Bienvenut, D. Sumpton, A. Martinez, S. Lilla, C. Espagne, T. Meinnel, and C. Giglione (2012)
Mol. Cell. Proteomics 11, M111.015131
   Abstract »    Full Text »    PDF »
Structural insights into anaphase-promoting complex function and mechanism.
D. Barford (2011)
Phil Trans R Soc B 366, 3605-3624
   Abstract »    Full Text »    PDF »
N-Terminal Acetylation Acts as an Avidity Enhancer Within an Interconnected Multiprotein Complex.
D. C. Scott, J. K. Monda, E. J. Bennett, J. W. Harper, and B. A. Schulman (2011)
Science 334, 674-678
   Abstract »    Full Text »    PDF »
Molecular dynamics simulations of the Cx26 hemichannel: Evaluation of structural models with Brownian dynamics.
T. Kwon, A. L. Harris, A. Rossi, and T. A. Bargiello (2011)
J. Gen. Physiol. 138, 475-493
   Abstract »    Full Text »    PDF »
Plastid Proteome Assembly without Toc159: Photosynthetic Protein Import and Accumulation of N-Acetylated Plastid Precursor Proteins.
S. Bischof, K. Baerenfaller, T. Wildhaber, R. Troesch, P.-A. Vidi, B. Roschitzki, M. Hirsch-Hoffmann, L. Hennig, F. Kessler, W. Gruissem, et al. (2011)
PLANT CELL 23, 3911-3928
   Abstract »    Full Text »    PDF »
Structure of a Ternary Naa50p (NAT5/SAN) N-terminal Acetyltransferase Complex Reveals the Molecular Basis for Substrate-specific Acetylation.
G. Liszczak, T. Arnesen, and R. Marmorstein (2011)
J. Biol. Chem. 286, 37002-37010
   Abstract »    Full Text »    PDF »
Interplay Between N-Terminal Methionine Excision and FtsH Protease Is Essential for Normal Chloroplast Development and Function in Arabidopsis.
Z. Adam, F. Frottin, C. Espagne, T. Meinnel, and C. Giglione (2011)
PLANT CELL 23, 3745-3760
   Abstract »    Full Text »    PDF »
Proteome-derived Peptide Libraries Allow Detailed Analysis of the Substrate Specificities of N{alpha}-acetyltransferases and Point to hNaa10p as the Post-translational Actin N{alpha}-acetyltransferase.
P. Van Damme, R. Evjenth, H. Foyn, K. Demeyer, P.-J. De Bock, J. R. Lillehaug, J. Vandekerckhove, T. Arnesen, and K. Gevaert (2011)
Mol. Cell. Proteomics 10, M110.004580
   Abstract »    Full Text »    PDF »
Mass Spectrometric Analysis of Lysine Ubiquitylation Reveals Promiscuity at Site Level.
J. M. R. Danielsen, K. B. Sylvestersen, S. Bekker-Jensen, D. Szklarczyk, J. W. Poulsen, H. Horn, L. J. Jensen, N. Mailand, and M. L. Nielsen (2011)
Mol. Cell. Proteomics 10, M110.003590
   Abstract »    Full Text »    PDF »
iTRAQ Protein Profile Analysis of Arabidopsis Roots Reveals New Aspects Critical for Iron Homeostasis.
P. Lan, W. Li, T.-N. Wen, J.-Y. Shiau, Y.-C. Wu, W. Lin, and W. Schmidt (2011)
Plant Physiology 155, 821-834
   Abstract »    Full Text »    PDF »
The APC/C subunit Cdc16/Cut9 is a contiguous tetratricopeptide repeat superhelix with a homo-dimer interface similar to Cdc27.
Z. Zhang, K. Kulkarni, S. J. Hanrahan, A. J. Thompson, and D. Barford (2010)
EMBO J. 29, 3733-3744
   Abstract »    Full Text »    PDF »
Inhibition of Human Peptide Deformylase Disrupts Mitochondrial Function.
S. Escobar-Alvarez, J. Gardner, A. Sheth, G. Manfredi, G. Yang, O. Ouerfelli, M. L. Heaney, and D. A. Scheinberg (2010)
Mol. Cell. Biol. 30, 5099-5109
   Abstract »    Full Text »    PDF »
Mouse Dfa Is a Repressor of TATA-box Promoters and Interacts with the Abt1 Activator of Basal Transcription.
C. S. Brower, L. Veiga, R. H. Jones, and A. Varshavsky (2010)
J. Biol. Chem. 285, 17218-17234
   Abstract »    Full Text »    PDF »
When the Beginning Marks the End.
A. Mogk and B. Bukau (2010)
Science 327, 966-967
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882