Asymmetric Engagement of Dimeric CRL3 KBTBD4 by the Molecular Glue UM171 Licenses Degradation of HDAC1/2 Complexes
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Le résumé fourni par la source
UM171 is a potent small molecule agonist of ex vivo human hematopoietic stem cell (HSC) self-renewal, a process that is tightly controlled by epigenetic regulation. By co-opting KBTBD4, a substrate receptor of the CULLIN3-RING E3 ubiquitin ligase complex, UM171 promotes the degradation of members of the CoREST transcriptional corepressor complex, thereby limiting HSC attrition. However, the direct target and mechanism of action of UM171 remain unclear. Here, we reveal that UM171 acts as a molecular glue to induce high-affinity interactions between KBTBD4 and HDAC1 to promote the degradation of select HDAC1/2 corepressor complexes. Through proteomics and chemical inhibitor studies, we discover that the principal target of UM171 is HDAC1/2. Cryo-electron microscopy (cryo-EM) analysis of dimeric KBTBD4 bound to UM171 and the LSD1-HDAC1-CoREST complex unveils an unexpected asymmetric assembly, in which a single UM171 molecule enables a pair of KBTBD4 KELCH-repeat propeller domains to recruit HDAC1 by clamping on its catalytic domain. One of the KBTBD4 propellers partially masks the rim of the HDAC1 active site pocket, which is exploited by UM171 to extend the E3-neo-substrate interface. The other propeller cooperatively strengthens HDAC1 binding via a separate and distinct interface. The overall neomorphic interaction is further buttressed by an endogenous cofactor of HDAC1-CoREST, inositol hexakisphosphate, which makes direct contacts with KBTBD4 and acts as a second molecular glue. The functional relevance of the quaternary complex interaction surfaces defined by cryo-EM is demonstrated by in situ base editor scanning of KBTBD4 and HDAC1. By delineating the direct target of UM171 and its mechanism of action, our results reveal how the cooperativity offered by a large dimeric CRL E3 family can be leveraged by a small molecule degrader and establish for the first time a dual molecular glue paradigm.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé, mais le titre doit être comparé manuellement.
- Titre Crossref
- Asymmetric Engagement of Dimeric CRL3 <sup>KBTBD4</sup> by the Molecular Glue UM171 Licenses Degradation of HDAC1/2 Complexes
- Date Crossref
- 14/05/2024
- Éditeur
- openRxiv
- Type
- posted-content
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Broad Institute pays non établi dans la noticeOrganisation à but non lucratif
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Harvard University Department of Chemistry and Chemical Biology pays non établi dans la noticeUniversité ou école supérieure
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Howard Hughes Medical Institute pays non établi dans la noticeStructure de recherche
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University of Washington Howard Hughes Medical Institute pays non établi dans la noticeUniversité ou école supérieure
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Brigham and Women's Hospital Department of Medicine pays non établi dans la noticeÉtablissement de santé
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Massachusetts General Hospital Center for Systems Biology pays non établi dans la noticeÉtablissement de santé
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Center for Systems Biology pays non établi dans la noticeStructure de recherche
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Center for Cancer Research pays non établi dans la noticeStructure de recherche
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University of Pavia Department of Biology and Biotechnology Lazzaro Spallanzani pays non établi dans la noticeUniversité ou école supérieure
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Department of Medicine pays non établi dans la noticeInstitution
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Department of Biological Chemistry and Molecular Pharmacology pays non établi dans la noticeInstitution
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Harvard T.H. Chan School of Public Health pays non établi dans la noticeUniversité ou école supérieure
Broad Institute, Department of Chemistry and Chemical Biology — Harvard University et Howard Hughes Medical Institute, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.