The RING domain of MUL1 (RING ) alone mediates ubiquitylation of the p53-transactivation domain (TAD ). To elucidate the mechanism underlying the simultaneous recruitment of UBE2D2 and the substrate TAD by RING , we determined the complex structure of RING :UBE2D2 and studied the interaction between RING and TAD in the presence of UBE2D2-UB thioester (UBE2D2~UB) mimetics. The RING -binding induced the closed conformation of UBE2D2 -UB oxyester (UBE2D2 -UB ), and strongly accelerated its hydrolysis, which was suppressed by the additional N77A-mutation of UBE2D2. Interestingly, UBE2D2 -UB oxyester (UBE2D2 -UB ) already formed a closed conformation in the absence of RING . Although TAD exhibited weak binding for RING or UBE2D2 alone, its binding affinity was enhanced and even further for RING :UBE2D2 and RING :UBE2D2 -UB , respectively. The recognition of TAD by RING as a complex with UBE2D2~UB is related to the multivalency of the binding events and underlies the ability of RING to ubiquitylate the intrinsically disordered protein, TAD .
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