Structural variation of types IV-A1- and IV-A3-mediated CRISPR interference

R. Čepaitė, N. Klein, A. Mikšys, S. Camara-Wilpert, V. Ragožius, F. Benz, A. Skorupskaitė, H. Becker, G. Žvejytė, N. Steube, Hochberg G.K.a, L. Randau, R. Pinilla-Redondo, L. Malinauskaitė () and P. Pausch ()
Additional contact information
R. Čepaitė: Vilnius University
N. Klein: Philipps-Universität Marburg
A. Mikšys: Vilnius University
S. Camara-Wilpert: University of Copenhagen
V. Ragožius: Vilnius University
F. Benz: Université Paris Cité, CNRS UMR6047
A. Skorupskaitė: Vilnius University
H. Becker: Philipps-Universität Marburg
G. Žvejytė: Vilnius University
N. Steube: Max Planck Institute for Terrestrial Microbiology
Hochberg G.K.a: Max Planck Institute for Terrestrial Microbiology
L. Randau: Philipps-Universität Marburg
R. Pinilla-Redondo: University of Copenhagen
L. Malinauskaitė: Vilnius University
P. Pausch: Vilnius University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract CRISPR-Cas mediated DNA-interference typically relies on sequence-specific binding and nucleolytic degradation of foreign genetic material. Type IV-A CRISPR-Cas systems diverge from this general mechanism, using a nuclease-independent interference pathway to suppress gene expression for gene regulation and plasmid competition. To understand how the type IV-A system associated effector complex achieves this interference, we determine cryo-EM structures of two evolutionarily distinct type IV-A complexes (types IV-A1 and IV-A3) bound to cognate DNA-targets in the presence and absence of the type IV-A signature DinG effector helicase. The structures reveal how the effector complexes recognize the protospacer adjacent motif and target-strand DNA to form an R-loop structure. Additionally, we reveal differences between types IV-A1 and IV-A3 in DNA interactions and structural motifs that allow for in trans recruitment of DinG. Our study provides a detailed view of type IV-A mediated DNA-interference and presents a structural foundation for engineering type IV-A-based genome editing tools.

Date: 2024
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DOI: 10.1038/s41467-024-53778-1

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