p-IRAK2:K63-linked pUb oligo-TRAF6 p-IRAK2:oligo-TRAF6 Auto ubiquitination of oligo-TRAF6 bound to p-IRAK2 at endosome membrane Authored: Shamovsky, V, 2010-06-01 EC Number: 6.3.2.19 Edited: Shamovsky, V, 2010-11-15 Pubmed17135271 Reactome Database ID Release 43975147 Reactome, http://www.reactome.org ReactomeREACT_24996 Reviewed: Gillespie, ME, 2010-10-29 TRAF6 possesses ubiquitin ligase activity and undergoes K-63-linked auto-ubiquitination after its oligomerization. In the first step, ubiquitin is activated by an E1 ubiquitin activating enzyme. The activated ubiquitin is transferred to a E2 conjugating enzyme (a heterodimer of proteins Ubc13 and Uev1A) forming the E2-Ub thioester. Finally, in the presence of ubiquitin-protein ligase E3 (TRAF6, a RING-domain E3), ubiquitin is attached to the target protein (TRAF6 on residue Lysine 124) through an isopeptide bond between the C-terminus of ubiquitin and the epsilon-amino group of a lysine residue in the target protein. In contrast to K-48-linked ubiquitination that leads to the proteosomal degradation of the target protein, K-63-linked polyubiquitin chains act as a scaffold to assemble protein kinase complexes and mediate their activation through proteosome-independent mechanisms. This K63 polyubiquitinated TRAF6 activates the TAK1 kinase complex. has a Stoichiometric coefficient of 9 ubiquitin