Anti-CRISPR AcrIIC3 discriminates between Cas9 orthologs via targeting the variable surface of the HNH nuclease domain

The FEBS Journal
Youngim KimJeong-Yong Suh

Abstract

CRISPR-Cas systems constitute the adaptive immunity of bacteria and archaea, degrading nucleic acids of invading phages and plasmids. In response, phages employ anti-CRISPR (Acr) proteins as a counter-defense mechanism to neutralize the host immunity. AcrIIC3 directly inhibits target DNA cleavage of type II-C Cas9 of Neisseria meningitidis. Here we show that AcrIIC3 interacts with the HNH nuclease domain of N. meningitidis Cas9 to inhibit its nuclease activity in an allosteric manner. The crystal structure of the AcrIIC3-HNH complex reveals that AcrIIC3 binds opposite the active site on the HNH nuclease domain. AcrIIC3 employs a unique interface for HNH, allowing it to discriminate between Cas9 orthologs, which contrasts with the broad spectrum of Cas9 inhibition by AcrIIC1. Interface residues of HNH provide key electrostatic and hydrophobic interactions that determine the host specificity of AcrIIC3. Mutations that replace HNH interfaces of N. meningitidis Cas9 with those of Geobacillus stearothermophilus Cas9 or Campylobacter jejuni Cas9 significantly attenuate AcrIIC3 binding, illustrating that the divergent interaction surface confers the host specificity of AcrIIC3. Our study demonstrates that the variable sequences of bin...Continue Reading

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Citations

Mar 21, 2020·Biochemical Society Transactions·Pierre Hardouin, Adeline Goulet
Jun 17, 2020·Nucleic Acids Research·So Young AnJeong-Yong Suh
Mar 19, 2020·Annual Review of Biochemistry·Alan R DavidsonErik J Sontheimer
Jun 7, 2020·Annual Review of Microbiology·Tanner WiegandBlake Wiedenheft
Sep 30, 2020·RNA Biology·Yadan Zhang, Mario Andrea Marchisio
Dec 11, 2020·The FEBS Journal·W Brent Derry
Mar 2, 2021·Biochemical Pharmacology·Christopher L BarkauKeith T Gagnon
Mar 25, 2021·The FEBS Journal·Alexander Wlodawer
Jun 6, 2021·Nature Reviews. Molecular Cell Biology·Ning Jia, Dinshaw J Patel
Oct 23, 2021·Protein Science : a Publication of the Protein Society·Gi Eob KimHyun Ho Park

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