Atomic Structures of Anthrax Prechannel Bound with Full-Length Lethal and Edema Factors
- Structure. 2020 Aug 4;28(8):879-887.e3. doi: 10.1016/j.str.2020.05.009.
- 1. California NanoSystems Institute, University of California, Los Angeles, CA 90095, USA.
- 2. California NanoSystems Institute, University of California, Los Angeles, CA 90095, USA; Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA.
- 3. Department of Microbial Pathogenesis, University of Maryland, Baltimore, Baltimore, MD 21201, USA.
- 4. Department of Microbial Pathogenesis, University of Maryland, Baltimore, Baltimore, MD 21201, USA. Electronic address: [email protected].
- 5. California NanoSystems Institute, University of California, Los Angeles, CA 90095, USA; Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA. Electronic address: [email protected].
Pathogenesis of anthrax disease involves two cytotoxic enzymes-edema factor (EF) and lethal factor (LF)-which are individually recruited by the protective antigen heptamer (PA7) or octamer (PA8) prechannel and subsequently translocated across channels formed on the endosomal membrane upon exposure to low pH. Here, we report the atomic structures of PA8 prechannel-bound full-length EF and LF. In this pretranslocation state, the N-terminal segment of both factors refolds into an α helix engaged in the α clamp of the prechannel. Recruitment to the PA prechannel exposes an originally buried β strand of both toxins and enables domain organization of EF. Many interactions occur on domain interfaces in both PA prechannel-bound EF and LF, leading to toxin compaction prior to translocation. Our results provide key insights into the molecular mechanisms of translocation-coupled protein unfolding and translocation.