Molecular and Structural Characterization of Lenalidomide-Mediated Sequestration of eIF3i.
Molecular and Structural Characterization of Lenalidomide-Mediated Sequestration of eIF3i.
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DOI：
10.1021/acschembio.2c00706
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发表时间：
2022-11-18
影响因子：
4
通讯作者：
Woo, Christina M.
中科院分区：
文献类型：
--
作者：
Lin, Zhi;Shen, Dacheng;Yang, Bo;Woo, Christina M.
来那度胺是E3连接酶底物适配器Cereblon(CRBN)的一种配体，其临床作用部分是通过促进底物募集和降解来实现的。与以前的靶点不同，eIF3i在与来那度胺和CRBN形成复杂的化合物时被招募，但不被降解，尽管这种相互作用的结构细节和机制结果尚未解决。在这里，我们描述了来那度胺诱导的eIF3i从eIF3复合体中分离的结构基础和机制结果。通过共价来那度胺探针和质谱学鉴定eIF3i上的结合界面，使隔离事件合理化。我们进一步将eIF3i和CRBN与来那度胺对血管生成标记物、Akt1磷酸化和相关的抗血管生成表型的影响联系起来。最后，我们发现在MM.1S和MOLM13细胞中，eIF3i在其他底物如IKZF1降解后观察到eIF3i的隔离。化学蛋白质组学阐明了已定义的结合界面，并观察到eIF3i隔离作为来那度胺的功能，这为设计新的蛋白质隔离的化学适配器作为选择性控制蛋白质功能的策略开辟了未来的方向。
Lenalidomide is a ligand of the E3 ligase substrate adapter cereblon (CRBN) that achieves its clinical effects in part by promotion of substrate recruitment and degradation. In contrast to prior targets, eIF3i is recruited but not degraded upon complex formation with lenalidomide and CRBN, although the structural details and mechanistic outcomes of this interaction are unresolved. Here, we characterize the structural basis and mechanistic outcomes of lenalidomide-induced sequestration of eIF3i from the eIF3 complex. Identification of the binding interface on eIF3i by a covalent lenalidomide probe and mass spectrometry rationalizes the sequestration event. We further connect eIF3i and CRBN to lenalidomide-driven effects on angiogenic markers, Akt1 phosphorylation, and associated antiangiogenesis phenotypes. Finally, we find that eIF3i sequestration is observed in MM.1S and MOLM13 cells after the degradation of other substrates, such as IKZF1. The defined binding interface elucidated by chemical proteomics, and the observation of eIF3i sequestration as a lenalidomide function opens future directions in designing new chemical adapters for protein sequestration as a strategy to selectively control protein functions.
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影响因子：
14.9
作者：
Eliseev B;Yeramala L;Leitner A;Karuppasamy M;Raimondeau E;Huard K;Alkalaeva E;Aebersold R;Schaffitzel C
通讯作者：
Schaffitzel C
DOI：
10.1096/fj.201903060rr
发表时间：
2020-09
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
--
作者：
Beedie SL;Huang PA;Harris EM;Strope JD;Mahony C;Chau CH;Vargesson N;Figg WD
通讯作者：
Figg WD
DOI：
10.1126/science.aab1433
发表时间：
2015-06-19
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Winter GE;Buckley DL;Paulk J;Roberts JM;Souza A;Dhe-Paganon S;Bradner JE
通讯作者：
Bradner JE
影响因子：
78.8
作者：
Huinen, Zowi R.;Huijbers, Elisabeth J. M.;Griffioen, Arjan W.
通讯作者：
Griffioen, Arjan W.
影响因子：
3.1
作者：
Dredge, K;Horsfall, R;Bartlett, JB
通讯作者：
Bartlett, JB