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PreprintCited by 14Bacteriophages and microbial interactionsCRISPR and Genetic EngineeringBacterial Genetics and Biotechnology

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Structure and Activation Mechanism of a Lamassu Phage Defence System

Open access
Li, Yan, Adams, David W., Liu, Hon Wing, Shaw, Steven J., Uchikawa, Emiko, Jaskólska, Milena, Stutzmann, Sandrine, Righi, Laurie, Szczelkun, Mark D., Blokesch, Melanie, Gruber, Stephan·2025·Nature Structural & Molecular Biology
DOI 10.1101/2025.03.14.643221

Preprint — published as 10.1038/s41594-025-01677-4 · Paper page

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Abstract

Summary: Lamassu is a diverse family of defence systems that protect bacteria, including pandemic strains of Vibrio cholerae , against phage infection. They target essential cellular processes, aborting infection and preventing phage propagation by terminating the infected host. The mechanisms by which Lamassu efectors are activated when needed and otherwise suppressed are unknown. Here, we present structures of a Lamassu defence system from Salmonella enterica . We show that an oligomerization domain of the nuclease efector, LmuA, is sequestered by two tightly-folded SMC-like LmuB protomers and LmuC. Upon activation, liberated LmuA proteins assemble into a cyclic homo-tetramer, in which two of four nuclease domains are brought into proximity to create an active site capable of cleaving DNA. We propose tetramer formation is likely a one-way switch that establishes a threshold to limit potential spontaneous activation and cell death. Our findings reveal a mechanism of cellular defence, involving liberation and oligomerization of immune efectors, and shed light on how Lamassu systems balance potent immune responses with self-preservation.

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Metadata

Authors
Li, Y., Adams, D. W., Liu, H. W., Shaw, S. J., Uchikawa, E., Jaskólska, M., Stutzmann, S., Righi, L., Szczelkun, M. D., Blokesch, M., & Gruber, S.
Affiliations
  • University of Lausanne (CH)
  • École Polytechnique Fédérale de Lausanne (CH)
  • University of Bristol (GB)
Corresponding author
Gruber, Stephan
ORCID
Venue
Nature Structural & Molecular Biology
Publisher
openRxiv
Published
2025-03-15
Volume
32
Issue
12
Pages
2503-2516
ISSN
1545-9985 (ISSN-L)
DOI
10.1101/2025.03.14.643221
OpenAlex
W4415143508
Cited by
14
References
1
Citations by year
2026: 9 · 2025: 5
FWCI
7.38
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Structural & Molecular Biology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • Bristol Research (University of Bristol) (acceptedVersion, cc-by)
  • Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
  • IRIS (submittedVersion)
Topics
  • Life Sciences › Immunology and Microbiology › Virology › Bacteriophages and microbial interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
Keywords
phage defense, plasmid defense, Salmonella enterica, protein oligomerization, tetramer formation, DNA cleavage, protein structure, Vibrio cholerae, bacterial immunity
MeSH terms
Bacterial Proteins, Bacteriophages, Models, Molecular, Plasmids, Vibrio cholerae, Crystallography, X-Ray, Salmonella enterica, Protein Multimerization

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