Structure-guided discovery of anti-CRISPR and anti-phage defense proteins

Ning Duan, Emily Hand, Mannuku Pheko, Shikha Sharma and Akintunde Emiola ()
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Ning Duan: National Institutes of Health
Emily Hand: National Institutes of Health
Mannuku Pheko: National Institutes of Health
Shikha Sharma: National Institutes of Health
Akintunde Emiola: National Institutes of Health

Nature Communications, 2024, vol. 15, issue 1, 1-10

Abstract: Abstract Bacteria use a variety of defense systems to protect themselves from phage infection. In turn, phages have evolved diverse counter-defense measures to overcome host defenses. Here, we use protein structural similarity and gene co-occurrence analyses to screen >66 million viral protein sequences and >330,000 metagenome-assembled genomes for the identification of anti-phage and counter-defense systems. We predict structures for ~300,000 proteins and perform large-scale, pairwise comparison to known anti-CRISPR (Acr) and anti-phage proteins to identify structural homologs that otherwise may not be uncovered using primary sequence search. This way, we identify a Bacteroidota phage Acr protein that inhibits Cas12a, and an Akkermansia muciniphila anti-phage defense protein, termed BxaP. Gene bxaP is found in loci encoding Bacteriophage Exclusion (BREX) and restriction-modification defense systems, but confers immunity independently. Our work highlights the advantage of combining protein structural features and gene co-localization information in studying host-phage interactions.

Date: 2024
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DOI: 10.1038/s41467-024-45068-7

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