title: The N-end rule pathway is mediated by a complex of the RING-type Ubr1 and HECT-type Ufd4 ubiquitin ligases.
abstract: Substrates of the N-end rule pathway are recognized by the Ubr1 E3 ubiquitin ligase through their destabilizing amino-terminal residues. Our previous work showed that the Ubr1 E3 and the Ufd4 E3 together target an internal degradation signal (degron) of the Mgt1 DNA repair protein. Ufd4 is an E3 enzyme of the ubiquitin-fusion degradation (UFD) pathway that recognizes an N-terminal ubiquitin moiety. Here we show that the RING-type Ubr1 E3 and the HECT-type Ufd4 E3 interact, both physically and functionally. Although Ubr1 can recognize and polyubiquitylate an N-end rule substrate in the absence of Ufd4, the Ubr1-Ufd4 complex is more processive in that it produces a longer substrate-linked polyubiquitin chain. Conversely, Ubr1 can function as a polyubiquitylation-enhancing component of the Ubr1-Ufd4 complex in its targeting of UFD substrates. We also found that Ubr1 can recognize the N-terminal ubiquitin moiety. These and related advances unify two proteolytic systems that have been studied separately for two decades.
authors.affiliation: Division of Biology, California Institute of Technology, Pasadena, California 91125, USA.
authors.forename: Cheol-Sang
authors.initials: CS
authors.lastname: Hwang
authors.forename: Anna
authors.initials: A
authors.lastname: Shemorry
authors.forename: Daniel
authors.initials: D
authors.lastname: Auerbach
authors.forename: Alexander
authors.initials: A
authors.lastname: Varshavsky
mesh_terms: D018398:Homeodomain Proteins / Q000378:metabolism; D053858:Metabolic Networks and Pathways; D010447:Peptide Hydrolases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C090457:CUP9 protein, S cerevisiae; D018398:Homeodomain Proteins; D011506:Proteins; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; C509339:Ufd4 protein, S cerevisiae; C066066:UBR1 protein, S cerevisiae; D044767:Ubiquitin-Protein Ligases; D010447:Peptide Hydrolases