Allosteric degraders induce CRL5ASB8 mediated degradation of XPO1

Hudman-Wing, C. E.; Fung, H. Y. J.; Cagatay, T.; Kwanten, B.; Niesman, A. B.; Gharghabi, M.; Permentier, B.; Shakya, B.; Shacham, S.; Landesman, Y.; Lapalombella, R.; Daelemans, D.; Chook, Y. M.

doi:10.1101/2024.10.07.617049

bioRxiv · 10.1101/2024.10.07.617049

Allosteric degraders induce CRL5ASB8 mediated degradation of XPO1

Hudman-Wing, C. E.·Fung, H. Y. J.·Cagatay, T.·Kwanten, B.·Niesman, A. B.·Gharghabi, M.·Permentier, B.·Shakya, B.·Shacham, S.·Landesman, Y.·Lapalombella, R.·Daelemans, D.·Chook, Y. M.

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Abstract

SummaryThe nuclear export receptor exportin 1 (XPO1/CRM1) is often overexpressed in cancer cells, leading to the mislocalization of numerous cancer-related protein cargoes1,2. Selinexor, a covalent XPO1 inhibitor, and other Selective Inhibitor of Nuclear Export (SINEs) restore proper nuclear localization by blocking XPO1-cargo binding2-7. SINEs also induce XPO1 degradation via the Cullin-RING E3 ubiquitin ligase (CRL) substrate receptor ASB87. Here we elucidate the mechanism underlying the high-affinity engagement of CRL5ASB8 with SINE-conjugated XPO1. Cryogenic electron microscopy (cryoEM) structures reveal that ASB8 binds to a cryptic site on XPO1, which becomes accessible only upon SINE conjugation. While molecular glue degraders typically interact with both CRL and the substrate8-10, SINEs bind to XPO1 without requiring interaction with ASB8 for efficient XPO1 degradation. Instead, an allosteric mechanism facilitates high affinity XPO1-ASB8 interaction, leading to XPO1 ubiquitination and degradation. ASB8-mediated degradation is also observed upon treatment of the endogenous itaconate derivate 4-octyl itaconate, which suggests a native mechanism that is inadvertently exploited by synthesized XPO1 inhibitors. This allosteric XPO1 degradation mechanism of SINE compounds expands the known modes of targeted protein degradation beyond the well-characterized molecular glue degraders and proteolysis targeting chimeras of CRL4.

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Hudman-Wing, C. E., Fung, H. Y. J., Cagatay, T., Kwanten, B., Niesman, A. B., Gharghabi, M., Permentier, B., Shakya, B., Shacham, S., Landesman, Y., Lapalombella, R., Daelemans, D., Chook, Y. M.. 2024-10-11. Allosteric degraders induce CRL5ASB8 mediated degradation of XPO1. https://doi.org/10.1101/2024.10.07.617049

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