Abstract
Bacteria encode hundreds of diverse defence systems that protect them from viral infection and inhibit phage propagation1–5. Gabija is one of the most prevalent anti-phage defence systems, occurring in more than 15% of all sequenced bacterial and archaeal genomes1,6,7, but the molecular basis of how Gabija defends cells from viral infection remains poorly understood. Here we use X-ray crystallography and cryo-electron microscopy (cryo-EM) to define how Gabija proteins assemble into a supramolecular complex of around 500 kDa that degrades phage DNA. Gabija protein A (GajA) is a DNA endonuclease that tetramerizes to form the core of the anti-phage defence complex. Two sets of Gabija protein B (GajB) dimers dock at opposite sides of the complex and create a 4:4 GajA–GajB assembly (hereafter, GajAB) that is essential for phage resistance in vivo. We show that a phage-encoded protein, Gabija anti-defence 1 (Gad1), directly binds to the Gabija GajAB complex and inactivates defence. A cryo-EM structure of the virally inhibited state shows that Gad1 forms an octameric web that encases the GajAB complex and inhibits DNA recognition and cleavage. Our results reveal the structural basis of assembly of the Gabija anti-phage defence complex and define a unique mechanism of viral immune evasion.
| Original language | English |
|---|---|
| Pages (from-to) | 360-365 |
| Number of pages | 6 |
| Journal | Nature |
| Volume | 625 |
| Issue number | 7994 |
| Early online date | 22 Nov 2023 |
| DOIs | |
| Publication status | Published - 11 Jan 2024 |
Bibliographical note
We thank J. Asnes, J. Grippen and members of the P.J.K. and R.S. laboratories for comments and discussion, and A. Lu for assistance with X-ray data collection. The work was funded by grants to P.J.K. from the Pew Biomedical Scholars program, the Burroughs Wellcome Fund PATH program, the Mathers Foundation, the Mark Foundation for Cancer Research, the Cancer Research Institute, the Parker Institute for Cancer Immunotherapy and the National Institutes of Health (1DP2GM146250-01), and by grants to R.S. from the European Research Council (ERC-AdG GA 101018520), the Israel Science Foundation (MAPATS grant 2720/22), the Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine, the Deutsche Forschungsgemeinschaft (SPP 2330, grant 464312965) and the Knell Family Center for Microbiology. E.Y. is supported by the Clore Scholars Program and in part by the Israeli Council for Higher Education (CHE) via the Weizmann Data Science Research Center. A.G.J. is supported by a Life Science Research Foundation postdoctoral fellowship of the Open Philanthropy Project. X-ray data were collected at the Northeastern Collaborative Access Team beamlines 24-ID-C and 24-ID-E (P30 GM124165), and used a Pilatus detector (S10RR029205), an Eiger detector (S10OD021527) and the Argonne National Laboratory Advanced Photon Source (DE-AC02-06CH11357). Cryo-EM data were collected at the Harvard Cryo-EM Center for Structural Biology at Harvard Medical School. We thank T. Humphreys for help with cryo-EM data collection. Part of this research was supported by the NIH grant U24GM129547 and was performed at the Pacific Northwest Center for Cryo-EM at Oregon Health & Science University, with access through EMSL (grid.436923.9), a DOE Office of Science User Facility sponsored by the Office of Biological and Environmental Research.Publisher Copyright:
© 2023, The Author(s).
All Science Journal Classification (ASJC) codes
- General