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MUL1‐RING recruits the substrate, p53‐TAD as a complex with UBE2D2–UB conjugate
Author(s) -
Lee MinSung,
Lee SangOk,
Choi Joonhyeok,
Ryu Minju,
Lee MiKyung,
Kim JiHun,
Hwang Eunha,
Lee ChongKil,
Chi SeungWook,
Ryu KyoungSeok
Publication year - 2022
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.16360
Subject(s) - transactivation , conjugate , biophysics , substrate (aquarium) , ring (chemistry) , ubiquitin , stereochemistry , microbiology and biotechnology , biology , biochemistry , chemistry , transcription factor , gene , ecology , mathematics , organic chemistry , mathematical analysis
The RING domain of MUL1 (RING MUL1 ) alone mediates ubiquitylation of the p53‐transactivation domain (TAD p53 ). To elucidate the mechanism underlying the simultaneous recruitment of UBE2D2 and the substrate TAD p53 by RING MUL1 , we determined the complex structure of RING MUL1 :UBE2D2 and studied the interaction between RING MUL1 and TAD p53 in the presence of UBE2D2–UB thioester (UBE2D2~UB) mimetics. The RING MUL1 ‐binding induced the closed conformation of UBE2D2 S22R/C85S –UB K48R oxyester (UBE2D2 RS –UB R OE ), and strongly accelerated its hydrolysis, which was suppressed by the additional N77A‐mutation of UBE2D2. Interestingly, UBE2D2 S22R/N77A/C85S –UB K48R oxyester (UBE2D2 RAS –UB R OE ) already formed a closed conformation in the absence of RING MUL1 . Although TAD p53 exhibited weak binding for RING MUL1 or UBE2D2 alone, its binding affinity was enhanced and even further for RING MUL1 :UBE2D2 and RING MUL1 :UBE2D2 RAS –UB R OE , respectively. The recognition of TAD p53 by RING MUL1 as a complex with UBE2D2~UB is related to the multivalency of the binding events and underlies the ability of RING MUL1 to ubiquitylate the intrinsically disordered protein, TAD p53 .