Regulatory interactions between APOBEC3B N- and C-terminal domains

Braza, K.; Demir, O.; Ahn, S.-H.; Morris, C.; Calvo-Tusell, C.; McGuire, K.; Carpenter, M.; Chen, Y.; de la Pena Avalos, B.; Casalino, L.; Aihara, H.; Harris, R. S.; Amaro, R. E.

doi:10.1101/2024.12.11.628032

bioRxiv · 10.1101/2024.12.11.628032

Regulatory interactions between APOBEC3B N- and C-terminal domains

Braza, K.·Demir, O.·Ahn, S.-H.·Morris, C.·Calvo-Tusell, C.·McGuire, K.·Carpenter, M.·Chen, Y.·de la Pena Avalos, B.·Casalino, L.·Aihara, H.·Harris, R. S.·Amaro, R. E.

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Abstract

APOBEC3B (A3B) is implicated in DNA mutations that facilitate tumor evolution. Although structures of its individual N- and C-terminal domains (NTD and CTD) have been resolved through X-ray crystallography, the full-length A3B (fl-A3B) structure remains elusive, limiting understanding of its dynamics and mechanisms. In particular, the APOBEC3B C-terminal domain (A3Bctd) active site is frequently closed in models and structures. In this study, we built several new models of fl-A3B using integrative structural biology methods and selected a top model for further dynamical investigation. We compared dynamics of the truncated (A3Bctd) to the fl-A3B via conventional and Gaussian accelerated molecular dynamics (MD) simulations. Subsequently, we employed weighted ensemble methods to explore the fl-A3B active site opening mechanism, finding that interactions at the NTD-CTD interface enhance the opening frequency of the fl-A3B active site. Our findings shed light on the structural dynamics of fl-A3B, which may offer new avenues for therapeutic intervention in cancer.

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Braza, K., Demir, O., Ahn, S.-H., Morris, C., Calvo-Tusell, C., McGuire, K., Carpenter, M., Chen, Y., de la Pena Avalos, B., Casalino, L., Aihara, H., Harris, R. S., Amaro, R. E.. 2024-12-12. Regulatory interactions between APOBEC3B N- and C-terminal domains. https://doi.org/10.1101/2024.12.11.628032

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