9C1M | pdb_00009c1m

Architecture remodeling activates the HerA-DUF anti-phage defense system.

(2025) Mol Cell 85: 1189-1201.e5

• PubMed: 40010344 Search on PubMed
• DOI: https://doi.org/10.1016/j.molcel.2025.02.001
• Primary Citation of Related Structures:  
  9C1M, 9C1N, 9C1O, 9C1X, 9C5X


• PubMed Abstract: 
  

  Leveraging AlphaFold models and integrated experiments, we characterized the HerA-DUF4297 (DUF) anti-phage defense system, focusing on DUF's undefined biochemical functions. Guided by structure-based genomic analyses, we found DUF homologs to be universally distributed across diverse bacterial immune systems. Notably, one such homolog, Cap4, is a nuclease. Inspired by this evolutionary clue, we tested DUF's nuclease activity and observed that DUF cleaves DNA substrates only when bound to its partner protein HerA. To dissect the mechanism of DUF activation, we determined the structures of DUF and HerA-DUF. Although DUF forms large oligomeric assemblies both alone and with HerA, oligomerization alone was insufficient to elicit nuclease activity. Instead, HerA binding induces a profound architecture remodeling that propagates throughout the complex. This remodeling reconfigures DUF into an active nuclease capable of robust DNA cleavage. Together, we highlight an architecture remodeling-driven mechanism that may inform the activation of other immune systems.

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Organizational Affiliation: 

Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, OH 43210, USA; The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA; Program of OSBP, The Ohio State University, Columbus, OH 43210, USA; Center for RNA Biology, The Ohio State University, Columbus, OH 43210, USA.