Cryo-EM structure of AAV2 Rep68 bound to integration site AAVS1: insights into the mechanism of DNA melting

Jaiswal, Rahul; Braud, Brandon; Hernandez-Ramirez, Karen C.; Santosh, Vishaka; Washington, Alexander; Escalante, Carlos R.

doi:10.1093/nar/gkaf033

Title: Cryo-EM structure of AAV2 Rep68 bound to integration site AAVS1: insights into the mechanism of DNA melting

Journal Article · 29 January 2025 · Nucleic Acids Research

DOI: https://doi.org/10.1093/nar/gkaf033 · OSTI ID:2507362

Jaiswal, Rahul; Braud, Brandon; Hernandez-Ramirez, Karen C.; Santosh, Vishaka; Washington, Alexander;

Abstract The Rep68 protein from Adeno-Associated Virus (AAV) is a multifunctional SF3 helicase that performs most of the DNA transactions necessary for the viral life cycle. During AAV DNA replication, Rep68 assembles at the origin of replication, catalyzing the DNA melting and nicking reactions during the hairpin rolling replication process to complete the second-strand synthesis of the AAV genome. We report the cryo-electron microscopy structures of Rep68 bound to the adeno-associated virus integration site 1 in different nucleotide-bound states. In the nucleotide-free state, Rep68 forms a heptameric complex around DNA, with three origin-binding domains (OBDs) bound to the Rep-binding element sequence, while three remaining OBDs form transient dimers with them. The AAA+ domains form an open ring without interactions between subunits and DNA. We hypothesize that the heptameric structure is crucial for loading Rep68 onto double-stranded DNA. The ATPγS complex shows that only three subunits associate with the nucleotide, leading to a conformational change that promotes the formation of both intersubunit and DNA interactions. Moreover, three phenylalanine residues in the AAA+ domain induce a steric distortion in the DNA. Our study provides insights into how an SF3 helicase assembles on DNA and provides insights into the DNA melting process.

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Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER)

OSTI ID:: 2507362

Journal Information:: Nucleic Acids Research, Journal Name: Nucleic Acids Research Journal Issue: 3 Vol. 53; ISSN 0305-1048

Publisher:: Oxford University PressCopyright Statement

Country of Publication:: United Kingdom

Language:: English

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