Structural models of the MscL gating mechanism

Area of Science:

• Structural biology
• Biophysics
• Microbiology

Background:

• Mechanosensitive channels (MSCs) are critical for cellular mechanotransduction.
• The large conductance mechanosensitive channel (MscL) is a key bacterial MSC involved in osmotic pressure regulation.
• Understanding MscL gating is essential for deciphering cellular responses to mechanical stress.

Purpose of the Study:

• To develop three-dimensional structural models of MscL from Mycobacterium tuberculosis and Escherichia coli.
• To elucidate the gating mechanism of MscL in closed, intermediate, and open states.
• To investigate the spatial relationships between MscL structural components during channel opening.

Main Methods:

• Utilized crystal structure of M. tuberculosis MscL as a starting point.
• Developed computational models for closed, intermediate, and open MscL conformations.
• Modeled N-terminal residues (1-12) as an amphipathic alpha-helix (S1) forming a cytoplasmic gate.

Main Results:

• Proposed a gating mechanism involving an expandable transmembrane barrel (M1 and M2 helices) and a cytoplasmic gate (S1 helices).
• Demonstrated how increased membrane tension leads to increased tilt of M1 and M2 helices.
• Showed that S1 helices and C-terminal S3 helices dock parallel to the membrane during channel opening.

Conclusions:

• The developed MscL models provide critical insights into the gating mechanism.
• These models highlight the interplay between the transmembrane helices, cytoplasmic gate, and linking elements.
• The proposed mechanism is consistent with existing experimental data and modeling criteria.