Structural basis for broad anti-phage immunity by DISARM
Structural basis for broad anti-phage immunity by DISARM
In the evolutionary arms race against phage, bacteria have assembled a diverse arsenal of antiviral immune strategies. While the recently discovered DISARM (Defense Island System Associated with Restriction-Modification) systems can provide protection against a wide range of phage, the molecular mechanisms that underpin broad antiviral targeting but avoiding autoimmunity remain enigmatic. Here, we report cryo-EM structures of the core DISARM complex, DrmAB, both alone and in complex with an unmethylated phage DNA mimetic. These structures reveal that DrmAB core complex is autoinhibited by a trigger loop (TL) within DrmA and binding to DNA substrates containing a 5’ overhang dislodges the TL, initiating a long-range structural rearrangement for DrmAB activation. Together with structure-guided in vivo studies, our work provides insights into the mechanism of phage DNA recognition and specific activation of this widespread antiviral defense system.
Bravo, Jack P.K.
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Aparicio-Maldonado, Cristian
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Nobrega, Franklin L.
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Brouns, Stan J.J.
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Taylor, David W.
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December 2022
Bravo, Jack P.K.
b1cce6b3-e6e7-4661-b8c9-5dae65381a68
Aparicio-Maldonado, Cristian
56c97975-9aec-4357-8946-427c1005c67e
Nobrega, Franklin L.
6532795d-88a4-4f05-9b26-6af5b8f21a0d
Brouns, Stan J.J.
b9c93a6a-120b-476b-8394-048e41d8ae79
Taylor, David W.
cfa866c4-3420-44a6-9b2b-23b25b699dd0
Bravo, Jack P.K., Aparicio-Maldonado, Cristian, Nobrega, Franklin L., Brouns, Stan J.J. and Taylor, David W.
(2022)
Structural basis for broad anti-phage immunity by DISARM.
Nature Communications, 13 (1), [2987].
(doi:10.1101/2021.12.26.474123).
Abstract
In the evolutionary arms race against phage, bacteria have assembled a diverse arsenal of antiviral immune strategies. While the recently discovered DISARM (Defense Island System Associated with Restriction-Modification) systems can provide protection against a wide range of phage, the molecular mechanisms that underpin broad antiviral targeting but avoiding autoimmunity remain enigmatic. Here, we report cryo-EM structures of the core DISARM complex, DrmAB, both alone and in complex with an unmethylated phage DNA mimetic. These structures reveal that DrmAB core complex is autoinhibited by a trigger loop (TL) within DrmA and binding to DNA substrates containing a 5’ overhang dislodges the TL, initiating a long-range structural rearrangement for DrmAB activation. Together with structure-guided in vivo studies, our work provides insights into the mechanism of phage DNA recognition and specific activation of this widespread antiviral defense system.
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2021.12.26.474123v1.full
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In preparation date: 26 December 2021
e-pub ahead of print date: 27 May 2022
Published date: December 2022
Identifiers
Local EPrints ID: 456379
URI: http://eprints.soton.ac.uk/id/eprint/456379
ISSN: 2041-1723
PURE UUID: 7e0a0df9-f6e5-4e07-9331-601c4e2d9215
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Date deposited: 27 Apr 2022 15:23
Last modified: 15 Apr 2026 02:01
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Author:
Jack P.K. Bravo
Author:
Cristian Aparicio-Maldonado
Author:
Stan J.J. Brouns
Author:
David W. Taylor
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