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

Autor: Cory MB; Graduate Group in Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA., Li A; Department of Chemistry, University of Pennsylvania, Philadelphia, PA, USA., Hurley CM; Graduate Group in Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA., Carman PJ; Graduate Group in Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA., Pumroy RA; Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA., Hostetler ZM; Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Perez RM; Department of Chemistry, University of Pennsylvania, Philadelphia, PA, USA., Venkatesh Y; Department of Chemistry, University of Pennsylvania, Philadelphia, PA, USA., Li X; Department of Chemistry, University of Pennsylvania, Philadelphia, PA, USA., Gupta K; Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA., Petersson EJ; Department of Chemistry, University of Pennsylvania, Philadelphia, PA, USA. ejpetersson@sas.upenn.edu.; Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA. ejpetersson@sas.upenn.edu., Kohli RM; Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA. rkohli@pennmedicine.upenn.edu.; Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA. rkohli@pennmedicine.upenn.edu.
Jazyk: angličtina
Zdroj: Nature structural & molecular biology [Nat Struct Mol Biol] 2024 Oct; Vol. 31 (10), pp. 1522-1531. Date of Electronic Publication: 2024 May 16.
DOI: 10.1038/s41594-024-01317-3
Abstrakt: 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.
(© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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