The LexA-RecA* structure reveals a cryptic lock-and-key mechanism for SOS activation

Michael B Cory; Allen Li; Christina M Hurley; Peter J Carman; Ruth A Pumroy; Zachary M Hostetler; Ryann M Perez; Yarra Venkatesh; Xinning Li; Kushol Gupta; E James Petersson; Rahul M Kohli

doi:10.1038/s41594-024-01317-3

The LexA-RecA* structure reveals a cryptic lock-and-key mechanism for SOS activation

Nat Struct Mol Biol. 2024 May 16. doi: 10.1038/s41594-024-01317-3. Online ahead of print.

Authors

Affiliations

¹ Graduate Group in Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA.
² Department of Chemistry, University of Pennsylvania, Philadelphia, PA, USA.
³ Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA.
⁴ Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁵ Department of Chemistry, University of Pennsylvania, Philadelphia, PA, USA. ejpetersson@sas.upenn.edu.
⁶ Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA. ejpetersson@sas.upenn.edu.
⁷ Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA. rkohli@pennmedicine.upenn.edu.
⁸ Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA. rkohli@pennmedicine.upenn.edu.

PMID: 38755298
DOI: 10.1038/s41594-024-01317-3

Abstract

The bacterial SOS response plays a key role in adaptation to DNA damage, including genomic stress caused by antibiotics. SOS induction begins when activated RecA*, an oligomeric nucleoprotein filament that forms on single-stranded DNA, binds to and stimulates autoproteolysis of the repressor LexA. Here, we present the structure of the complete Escherichia coli SOS signal complex, constituting full-length LexA bound to RecA*. We uncover an extensive interface unexpectedly including the LexA DNA-binding domain, providing a new molecular rationale for ordered SOS gene induction. We further find that the interface involves three RecA subunits, with a single residue in the central engaged subunit acting as a molecular key, inserting into an allosteric binding pocket to induce LexA cleavage. Given the pro-mutagenic nature of SOS activation, our structural and mechanistic insights provide a foundation for developing new therapeutics to slow the evolution of antibiotic resistance.