Structural basis for broad anti-phage immunity by DISARM.

Area of Science:

• Molecular biology
• Bacteriophage-bacteria interactions
• Structural biology

Background:

• Bacteria possess diverse antiviral defense systems, including DISARM (Defense Island System Associated with Restriction-Modification) systems, to combat phage predation.
• The precise molecular mechanisms enabling DISARM systems' broad-spectrum phage targeting while preventing autoimmunity are not fully understood.

Purpose of the Study:

• To elucidate the structural basis for the broad antiviral activity and self-protection mechanisms of the DISARM system.
• To investigate the activation mechanism of the core DrmAB complex upon binding to phage DNA.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was used to determine the structures of the DrmAB complex.
• Structural analysis of the DrmAB complex alone and in complex with a phage DNA mimetic.
• Structure-guided in vivo experiments to validate functional mechanisms.

Main Results:

• The cryo-EM structures revealed that the DrmAB complex is autoinhibited by a trigger loop (TL) in DrmA.
• Binding of DNA substrates with a 5' overhang dislodges the TL, triggering a conformational change for DrmAB activation.
• The structures provide a molecular basis for how DISARM recognizes and is activated by phage DNA.

Conclusions:

• The DrmAB complex utilizes a trigger loop mechanism for autoinhibition and DNA-induced activation.
• This mechanism allows for specific recognition of foreign phage DNA, preventing autoimmune responses.
• The findings offer crucial insights into the functioning of a widespread bacterial antiviral defense system.