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Activation and self-inactivation mechanisms of the cyclic oligoadenylate-dependent CRISPR ribonuclease Csm6

Author

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  • Carmela Garcia-Doval

    (University of Zurich)

  • Frank Schwede

    (Biolog Life Science Institute GmbH & Co. KG)

  • Christian Berk

    (ETH Zurich)

  • Jakob T. Rostøl

    (The Rockefeller University)

  • Ole Niewoehner

    (University of Zurich)

  • Oliver Tejero

    (University of Zurich)

  • Jonathan Hall

    (ETH Zurich)

  • Luciano A. Marraffini

    (The Rockefeller University
    Howard Hughes Medical Institute, The Rockefeller University)

  • Martin Jinek

    (University of Zurich)

Abstract

Bacterial and archaeal CRISPR-Cas systems provide RNA-guided immunity against genetic invaders such as bacteriophages and plasmids. Upon target RNA recognition, type III CRISPR-Cas systems produce cyclic-oligoadenylate second messengers that activate downstream effectors, including Csm6 ribonucleases, via their CARF domains. Here, we show that Enteroccocus italicus Csm6 (EiCsm6) degrades its cognate cyclic hexa-AMP (cA6) activator, and report the crystal structure of EiCsm6 bound to a cA6 mimic. Our structural, biochemical, and in vivo functional assays reveal how cA6 recognition by the CARF domain activates the Csm6 HEPN domains for collateral RNA degradation, and how CARF domain-mediated cA6 cleavage provides an intrinsic off-switch to limit Csm6 activity in the absence of ring nucleases. These mechanisms facilitate rapid invader clearance and ensure termination of CRISPR interference to limit self-toxicity.

Suggested Citation

  • Carmela Garcia-Doval & Frank Schwede & Christian Berk & Jakob T. Rostøl & Ole Niewoehner & Oliver Tejero & Jonathan Hall & Luciano A. Marraffini & Martin Jinek, 2020. "Activation and self-inactivation mechanisms of the cyclic oligoadenylate-dependent CRISPR ribonuclease Csm6," Nature Communications, Nature, vol. 11(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15334-5
    DOI: 10.1038/s41467-020-15334-5
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    Cited by:

    1. Anna Nemudraia & Artem Nemudryi & Murat Buyukyoruk & Andrew M. Scherffius & Trevor Zahl & Tanner Wiegand & Shishir Pandey & Joseph E. Nichols & Laina N. Hall & Aidan McVey & Helen H. Lee & Royce A. Wi, 2022. "Sequence-specific capture and concentration of viral RNA by type III CRISPR system enhances diagnostic," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Shirin Fatma & Arpita Chakravarti & Xuankun Zeng & Raven H. Huang, 2021. "Molecular mechanisms of the CdnG-Cap5 antiphage defense system employing 3′,2′-cGAMP as the second messenger," Nature Communications, Nature, vol. 12(1), pages 1-9, December.

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