Mycolactone A vs. B: Multiscale Simulations Reveal the Roles of Localization and Association in Isomer-Specific...

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Mycolactone, an exotoxin from Mycobacterium ulcerans, causes Buruli ulcer by inhibiting the Sec61 translocon in the endoplasmic reticulum (ER).
• Two dominant mycolactone isoforms exist, but only one exhibits significant cytotoxicity.
• Understanding the structural basis for this differential cytotoxicity is crucial for developing targeted therapies.

Purpose of the Study:

• To investigate the molecular mechanisms underlying the differential cytotoxicity of mycolactone isoforms.
• To elucidate the specific interactions of mycolactone A and B with the ER membrane and the Sec61 translocon.

Main Methods:

• Extensive molecular dynamics (MD) simulations with enhanced free energy sampling.
• Utilized two distinct cryo-electron microscopy (cryo-EM) models of the Sec61 translocon.
• Analyzed toxin association with both the ER membrane and the Sec61 translocon.

Main Results:

• Mycolactone B exhibits stronger association with the ER membrane compared to mycolactone A, potentially increasing its proximity to the Sec61 translocon.
• Mycolactone B forms distinct interactions with the Sec61 translocon in different models, including closer contact with key residues for signal peptide recognition and with the translocon's lumenal and lateral gates.
• These interactions induce a closed translocon conformation, inhibiting protein translocation.

Conclusions:

• The enhanced cytotoxicity of mycolactone B is attributed to its increased localization to the ER membrane and its ability to induce a channel-locking association with the Sec61 translocon.
• These findings provide insights into Buruli ulcer pathogenesis and suggest potential therapeutic targets for diagnostics and Sec61-translocon-based treatments.