Identification of a consensus site for TRAF6/p62 polyubiquitination.
Tumor necrosis factor receptor-associated factor 6 (TRAF6) is an ubiquitin ligase that regulates a diverse array of physiological processes via forming Lys-63 linked polyubiquitin chains. In this study, the lysine selection process for TRAF6/p62 ubiquitination was examined. The protein sequence of two characterized TRAF6/p62 substrates, NRIF and TrkA, revealed a conserved consensus pattern for the ubiquitination site of these two TRAF6 substrates. The consensus pattern established in the verified substrates was common to the other Trk receptor family members, TrkB and TrkC. Interestingly, Lysine 811 in TrkB was selected for ubiquination, and mutation of Lysine 811 diminished the formation of TRAF6/p62 complex that is necessary for effective ubiquination. Moreover, downstream signaling was affected upon binding of BDNF to the mutant TrkB receptor. These findings reveal a possible selection process for targeting a specific lysine residue by a single E3 ligase and underscore the role of the scaffold, p62, in this process.
Jadhav
Trafina
T
Program in Cellular and Molecular Biosciences, Department of Biological Sciences, Auburn University, 331 Funchess Hall, Auburn, AL 36849, USA.
Geetha
Thangiah
T
Jiang
Jianxiong
J
Wooten
Marie W
MW
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D002460:Cell Line; D016384:Consensus Sequence; D006801:Humans; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D025821:Polyubiquitin / Q000378:metabolism*; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism; D020812:Receptor, trkC / Q000235:genetics / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D054875:Ubiquitination
D048868:Adaptor Proteins, Signal Transducing; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D048029:TNF Receptor-Associated Factor 6; D025821:Polyubiquitin; D020917:Receptor, trkA; D020813:Receptor, trkB; D020812:Receptor, trkC; D008239:Lysine