Structural mechanism of SAM-AMP and SAM-AMP₂ synthesis by the type III-D2 CRISPR effector complex.

Authors

Yoshihisa Mitsuda, Maki Sugaya, Junichiro Ishikawa, Naoto Nagahata, Sae Okazaki, Masahiro Hiraizumi, Kazuki Kato, Jonathan S Gootenberg, Omar O Abudayyeh, Tsuyoshi Osawa, Keitaro Yamashita, Hiroshi Nishimasu

Published in

Nature communications. Volume 17. Issue 1. Jun 24, 2026. Epub Jun 24, 2026.

Abstract

The type III-D2 CRISPR-Cas system comprises multiple Cas subunits and a CRISPR RNA, and is likely an evolutionary intermediate between the well-studied type III-A and III-E systems. Here we show that the type III-D2 complex synthesizes two distinct second messengers, SAM-AMP and SAM-AMP₂, from S-adenosylmethionine (SAM) and ATP in response to target RNA recognition. We determined cryo-electron microscopy structures of the type III-D2 effector complex in different functional states, providing mechanistic insights into target RNA cleavage and second messenger synthesis. The structures reveal how SAM and ATP are recognized by the Cas10 subunit within the effector complex. Furthermore, our biological data suggest that both SAM-AMP and SAM-AMP₂ act on the CorA ancillary effector, inducing growth arrest of infected bacterial cells and thereby conferring immunity. Thus, our study establishes the type III-D2 system as a unique anti-phage defense mechanism that employs both SAM-AMP and SAM-AMP₂ as second messengers, expanding the repertoire of second messenger strategies in bacterial defense systems and highlighting the remarkable functional diversity of CRISPR-Cas systems.

PMID:
42342668
Bibliographic data and abstract were imported from PubMed on 25 Jun 2026.

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