Jadhav Trafina, Geetha Thangiah, Jiang Jianxiong, Wooten Marie W
Program in Cellular and Molecular Biosciences, Department of Biological Sciences, Auburn University, 331 Funchess Hall, Auburn, AL 36849, USA.
Biochem Biophys Res Commun. 2008 Jul 4;371(3):521-4. doi: 10.1016/j.bbrc.2008.04.138. Epub 2008 May 5.
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.
肿瘤坏死因子受体相关因子6（TRAF6）是一种泛素连接酶，通过形成赖氨酸63连接的多聚泛素链来调节多种生理过程。在本研究中，对TRAF6/p62泛素化的赖氨酸选择过程进行了研究。两种已鉴定的TRAF6/p62底物NRIF和TrkA的蛋白质序列揭示了这两种TRAF6底物泛素化位点的保守共有模式。在已验证的底物中建立的共有模式在其他Trk受体家族成员TrkB和TrkC中也很常见。有趣的是，TrkB中的赖氨酸811被选择用于泛素化，赖氨酸811的突变减少了有效泛素化所必需的TRAF6/p62复合物的形成。此外，当脑源性神经营养因子（BDNF）与突变的TrkB受体结合时，下游信号传导受到影响。这些发现揭示了单个E3连接酶靶向特定赖氨酸残基的可能选择过程，并强调了支架蛋白p62在此过程中的作用。
