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UM171 glues asymmetric CRL3–HDAC1/2 assembly to degrade CoREST corepressors
Abstract UM171 is a potent agonist of ex vivo human haematopoietic stem cell self-renewal 1 . By co-opting KBTBD4, a substrate receptor of the CUL3–RING E3 ubiquitin ligase (CRL3) complex, UM171 promotes the degradation of the LSD1–CoREST corepressor complex, thereby limiting haematopoietic stem cell attrition 2,3 . However, the direct target and mechanism of action of UM171 remain unclear. Here we show that UM171 acts as a molecular glue to induce high-affinity interactions between KBTBD4 and HDAC1/2 to promote corepressor degradation. Through proteomics and chemical inhibitor studies, we identify the principal target of UM171 as HDAC1/2. Cryo-electron microscopy analysis of dimeric KBTBD4 bound to UM171 and the LSD1–HDAC1–CoREST complex identifies an asymmetric assembly in which a single UM171 molecule enables a pair of KELCH-repeat propeller domains to recruit the HDAC1 catalytic domain. One KBTBD4 propeller partially masks the rim of the HDAC1 active site, which is exploited by UM171 to extend the E3–neosubstrate interface. The other propeller cooperatively strengthens HDAC1 binding through a distinct interface. The overall CoREST–HDAC1/2–KBTBD4 interaction is further buttressed by the endogenous cofactor inositol hexakisphosphate, which acts as a second molecular glue. The functional relevance of the quaternary complex interaction surfaces is demonstrated by base editor scanning of KBTBD4 and HDAC1 . By delineating the direct target of UM171 and its mechanism of action, we reveal how the cooperativity offered by a dimeric CRL3 E3 can be leveraged by a small molecule degrader.
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Interplay of geometrical and spin chiralities in 3D twisted magnetic ribbons
Abstract Chirality is a ubiquitous and fundamental asymmetry in nature1,2. Recently, the interaction of chiral objects with spin currents has attracted enormous attention from both scientific and technological perspectives3–5. Of particular interest is the current-driven motion of chiral topological excitations such as chiral magnetic domain walls in chiral three-dimensional magnetic structures that could allow for high-density memory-storage devices. Here we use state-of-the-art multiphoton lithography6,7 to create three-dimensional chiral magnetic ribbons and perform current-induced motion of chiral domain walls. The ribbons are designed to have a clockwise or anticlockwise chiral twist with a variable magnitude. We find that domain walls can either pass through the ribbon or are impeded, depending on their chirality and configuration and the geometrical chiral twist of the ribbon. The interplay between the magnetic exchange energy and the geometrical twist generates a torsional field that favours chiral Bloch-type walls rather than the Néel-type wall favoured by the intrinsic magnetic properties of the magnetic ribbon itself. Furthermore, the interplay of spin chirality and chiral twist results in a non-reciprocal domain wall motion, namely, a domain wall filter or diode8–10. Our findings show how the interplay between geometrical and spin chiralities can lead to new functionalities that could allow for innovative chiral spintronics.