title: N-terminal acetylation acts as an avidity enhancer within an interconnected multiprotein complex.
abstract: 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.
authors.affiliation: Structural Biology Department, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Scott
authors.forename: Julie K
authors.initials: JK
authors.lastname: Monda
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Bennett
authors.forename: J Wade
authors.initials: JW
authors.lastname: Harper
authors.forename: Brenda A
authors.initials: BA
authors.lastname: Schulman
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D044842:Cullin Proteins / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000378:metabolism*; D000075687:NEDD8 Protein; D011485:Protein Binding; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D014452:Ubiquitins / Q000378:metabolism
chemical_list: C100318:Cullin 1; D044842:Cullin Proteins; C502135:Dcn1 protein, S cerevisiae; D046912:Multiprotein Complexes; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; C111706:RUB1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C112595:UBC12 protein, S cerevisiae; D014452:Ubiquitins; D044767:Ubiquitin-Protein Ligases