Structure of a tetrameric MscL in an expanded intermediate state

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Abstract
Mechanosensitive channels protect bacteria from osmotic shock by allowing ions to flow across the membrane in response to changes in membrane tension. MscL is one such channel with large conductance, which exhibits several intermediate states between its closed and open forms. The 3.8-Å crystal structure of the Staphylococcus aureus MscL has now been determined in a nonconductive, partially expanded and tetrameric form. Mechanosensitive channels protect bacteria from osmotic shock by allowing ions to flow across the membrane in response to changes in membrane tension. MscL is one such channel with a large conductance. Although understanding of its closed and open states has been increasing, little is known about the structures of the important intermediate states. Here, the 3.8 Å crystal structure of MscL in what is probably a non-conductive, partially expanded intermediate state, is presented. The ability of cells to sense and respond to mechanical force underlies diverse processes such as touch and hearing in animals, gravitropism in plants, and bacterial osmoregulation1,2. In bacteria, mechanosensation is mediated by the mechanosensitive channels of large (MscL), small (MscS), potassium-dependent (MscK) and mini (MscM) conductances. These channels act as ‘emergency relief valves’ protecting bacteria from lysis upon acute osmotic down-shock3. Among them, MscL has been intensively studied since the original identification and characterization 15 years ago4. MscL is reversibly and directly gated by changes in membrane tension. In the open state, MscL forms a non-selective 3 nS conductance channel which gates at tensions close to the lytic limit of the bacterial membrane. An earlier crystal structure at 3.5 Å resolution of a pentameric MscL from Mycobacterium tuberculosis represents a closed-state or non-conducting conformation5,6. MscL has a complex gating behaviour; it exhibits several intermediates between the closed and open states, including one putative non-conductive expanded state and at least three sub-conducting states7. Although our understanding of the closed5,6 and open8,9,10 states of MscL has been increasing, little is known about the structures of the intermediate states despite their importance in elucidating the complete gating process of MscL. Here we present the crystal structure of a carboxy-terminal truncation mutant (Δ95–120) of MscL from Staphylococcus aureus (SaMscL(CΔ26)) at 3.8 Å resolution. Notably, SaMscL(CΔ26) forms a tetrameric channel with both transmembrane helices tilted away from the membrane normal at angles close to that inferred for the open state9, probably corresponding to a non-conductive but partially expanded intermediate state.

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