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N-Terminal Acetylation Acts as an Avidity Enhancer Within an Interconnected Multiprotein Complex

Science, 4 November 2011
Vol. 334, Issue 6056, p. 674-678
DOI: 10.1126/science.1209307

N-Terminal Acetylation Acts as an Avidity Enhancer Within an Interconnected Multiprotein Complex

  1. Daniel C. Scott1,2,
  2. Julie K. Monda1,
  3. Eric J. Bennett3,*,
  4. J. Wade Harper3,
  5. Brenda A. Schulman1,2,
  1. 1Structural Biology Department, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.
  2. 2Howard Hughes Medical Institute, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.
  3. 3Cell Biology Department, Harvard Medical School, Boston, MA 02115, USA.
  1. To whom correspondence should be addressed. E-mail: brenda.schulman{at}
  1. * Present address: Division of Biological Sciences, University of California–San Diego, La Jolla, CA 92093, USA.


Although many eukaryotic proteins are amino (N)–terminally acetylated, structural mechanisms by which N-terminal acetylation mediates protein interactions are largely unknown. Here, we found that N-terminal acetylation of the E2 enzyme, Ubc12, dictates distinctive E3-dependent ligation of the ubiquitin-like protein Nedd8 to Cul1. Structural, biochemical, biophysical, and genetic analyses revealed how complete burial of Ubc12’s N-acetyl-methionine in a hydrophobic pocket in the E3, Dcn1, promotes cullin neddylation. The results suggest that the N-terminal acetyl both directs Ubc12’s interactions with Dcn1 and prevents repulsion of a charged N terminus. Our data provide a link between acetylation and ubiquitin-like protein conjugation and define a mechanism for N-terminal acetylation-dependent recognition.

  • Received for publication 3 June 2011.
  • Accepted for publication 9 September 2011.


D. C. Scott, J. K. Monda, E. J. Bennett, J. W. Harper, and B. A. Schulman, N-Terminal Acetylation Acts as an Avidity Enhancer Within an Interconnected Multiprotein Complex. Science 334, 674-678 (2011).

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