E2-BRCA1 RING interactions dictate synthesis of mono- or specific polyubiquitin chain linkages
E2-BRCA1 RING interactions dictate synthesis of mono- or specific polyubiquitin chain linkages
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DOI：
10.1038/nsmb1295
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发表时间：
2007-10-01
影响因子：
16.8
通讯作者：
Klevit, Rachel E.
中科院分区：
文献类型：
--
作者：
Christensen, Devin E.;Brzovic, Peter S.;Klevit, Rachel E.
E3泛素连接酶介导活化的泛素从E2泛素缀合酶转移到其底物赖氨酸残基。使用基于结构的酵母双杂交策略，我们发现了六个以前未鉴定的人异源二聚体环E3 BRCA 1-BARD 1和人E2 s UbcH 6，Ube 2 e2，UbcM 2，Ubc 13，Ube 2k和Ube 2 w之间的相互作用。所有6个E2直接结合BRCA 1 RING基序，并与BRCA 1-BARD 1在体外具有自泛素化活性。四个E2直接BRCA 1的单泛素化。Ubc 13-Mms 2和Ube 2k指导BRCA 1上Lys 63或Lys 48连接的泛素链的合成，并且需要与BRCA 1连接的受体泛素。BRCA 1相互作用E2的单泛素化和多泛素化活性之间的差异与它们在活性位点远端非共价结合泛素的能力相关。因此，BRCA 1有能力指导特定的多聚泛素链连接的合成，这取决于与其RING结合的E2。
An E3 ubiquitin ligase mediates the transfer of activated ubiquitin from an E2 ubiquitin-conjugating enzyme to its substrate lysine residues. Using a structure-based, yeast two-hybrid strategy, we discovered six previously unidentified interactions between the human heterodimeric RING E3 BRCA1-BARD1 and the human E2s UbcH6, Ube2e2, UbcM2, Ubc13, Ube2k and Ube2w. All six E2s bind directly to the BRCA1 RING motif and are active with BRCA1-BARD1 for autoubiquitination in vitro. Four of the E2s direct monoubiquitination of BRCA1. Ubc13-Mms2 and Ube2k direct the synthesis of Lys63- or Lys48-linked ubiquitin chains on BRCA1 and require an acceptor ubiquitin attached to BRCA1. Differences between the mono- and polyubiquitination activities of the BRCA1- interacting E2s correlate with their ability to bind ubiquitin noncovalently at a site distal to the active site. Thus, BRCA1 has the ability to direct the synthesis of specific polyubiquitin chain linkages, depending on the E2 bound to its RING.