Regulatory Interactions Between APOBEC3B N- and C-terminal Domains

Overview

Journal bioRxiv

Date 2024 Dec 23

PMID 39713448

Authors

Mac Kevin E Braza

Ozlem Demir

Surl-Hee Ahn

Clare K Morris

Carla Calvo-Tusell

Kelly L McGuire

Barbara de la Pena Avalos

Michael A Carpenter

Yanjun Chen

Lorenzo Casalino

Hideki Aihara

Mark A Herzik Jr

Reuben S Harris

Rommie E Amaro

Affiliations

Soon will be listed here.

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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