Structural Determinants of MscL Gating Studied by Molecular Dynamics Simulations

Gullingsrud, Justin; Kosztin, Dorina; Schulten, Klaus

doi:10.1016/s0006-3495(01)76181-4

Cited by 172 publications

(140 citation statements)

References 32 publications

Supporting

Mentioning

130

Contrasting

Order By: Relevance

“…11 The S1 in the revised version has a helical structure running parallel to the cytoplasmic membrane surface instead of In order to examine the structural changes during the opening of MscL in atomic detail, molecular simulations, including all atom and coarse-grained models, have been conducted. [20][21][22][23][24][25][26][27][28] The first problem to simulate channel opening is how to apply forces to a modeled MscL. One method employed force tethered to particular AAs or whole-channel proteins.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The gating mechanism of the bacterial mechanosensitive channel MscL revealed by molecular dynamics simulations

2012

View full text Add to dashboard Cite

Section: Introductionmentioning

confidence: 99%

“…One method employed force tethered to particular AAs or whole-channel proteins. 20,21,24,27 This method could somehow simulate MscL opening behaviors, but with some abnormal structural changes of MscL. Another method is to generate stress in the MscL-embedded membrane by modifying the bilayer structure.…”

Section: Introductionmentioning

confidence: 99%

The gating mechanism of the bacterial mechanosensitive channel MscL revealed by molecular dynamics simulations

2012

View full text Add to dashboard Cite

“…As in other gated ion channels with proposed hydrophobic gates (15,16), MscL also has a structurally open pore constriction in its closed form; functionally, however, it does not conduct ions. During gating, on the other hand, the solvent environment of the hydrophobic residues in the pore constriction changes (10,17) because of an irislike movement of TM1 helices, and the channel begins to conduct. According to hydrophobic gating theory, a minor change in the hydrophobicity of the pore lining should be enough to open such channels (15).…”

mentioning

confidence: 99%

Hydrophobic gating of mechanosensitive channel of large conductance evidenced by single-subunit resolution

Birkner

Poolman

Koçer

2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Mechanosensitive (MS) ion channels are membrane proteins that detect and respond to membrane tension in all branches of life. In bacteria, MS channels prevent cells from lysing upon sudden hypoosmotic shock by opening and releasing solutes and water. Despite the importance of MS channels and ongoing efforts to explain their functioning, the molecular mechanism of MS channel gating remains elusive and controversial. Here we report a method that allows single-subunit resolution for manipulating and monitoring "mechanosensitive channel of large conductance" from Escherichia coli. We gradually changed the hydrophobicity of the pore constriction in this homopentameric protein by modifying a critical pore residue one subunit at a time. Our experimental results suggest that both channel opening and closing are initiated by the transmembrane 1 helix of a single subunit and that the participation of each of the five identical subunits in the structural transitions between the closed and open states is asymmetrical. Such a minimal change in the pore environment seems ideal for a fast and energyefficient response to changes in the membrane tension. from Escherichia coli (Eco-MscL) is one of the best-characterized mechanosensitive channels (1, 2). It senses membrane tension invoked by sudden hypoosmotic stress and acts as an emergency valve by opening a large, transient, nonselective aqueous pore in the membrane. The crystal structure of the closed state of MscL from Mycobacterium tuberculosis (Tb-MscL) consists of five identical subunits. Each subunit has a helical cytoplasmic N terminus (S1), two transmembrane helices (TM1 and TM2) connected by a periplasmic loop (PL), and a bundle of cytoplasmic helix (CP). The closed channel has a pore diameter of about 3.5 Å (3). The estimated open pore diameter, on the other hand, is 30-40 Å (4, 5), suggesting that significant conformational changes take place upon gating.Despite a large body of experimental and theoretical data, the gating mechanism by which MscL physically opens and closes its permeation pathway is still unknown. Various molecular rearrangements have been proposed to underlie MscL gating. These include (i) a slight counterclockwise (6) or a large clockwise rotation (7) of the TM1 helices when viewed from the periplasm; (ii) a significant preexpansion of TM1 helices forming a closed/ expanded state followed by separation of S1 bundles (8); (iii) the separation of only the TM1 domains but not S1 domains as the primary energy barrier for gating (9, 10); and (iv) the rotation and shifting of TM1-TM2 pairs as a rigid body (11,12).Despite some discrepancies in details, there are two common elements in all models of MscL gating. The first is a hydrophobic pore constriction formed by a region on TM1 helices. In the crystal structure of Tb-MscL, the pore lumen is lined mainly by TM1 helices, and it narrows toward the cytoplasm. The narrowest part is formed by the fivefold symmetry of a hydrophobic, methylterminated motif (L17xxxV21) on TM1 helices (Fig. 1). Random mutagenesi...

show abstract

“…Significant efforts have been devoted to the understanding of the gating mechanisms of MscL (2,4,5,16,17). In recent combined experimental and modeling studies (18,19), the closed, open, and intermediate structures of TbMscL and EcoMscL have been proposed.…”

mentioning

confidence: 99%

Conformational pathways in the gating of Escherichia coli mechanosensitive channel

Kong

Shen

Warth

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The pathway of the gating conformational transition of Escherichia coli mechanosensitive channel was simulated, using the recently modeled open and closed structures, by targeted molecular dynamics method. The transition can be roughly viewed as a fourstage process. The initial motion under a lower tension load is predominantly elastic deformation. The opening of the inner hydrophobic pore on a higher tension load takes place after the major expansion of the outer channel dimension. The hypothetical N-terminal S1 helical bundle has been confirmed to form the hydrophobic gate, together with the M1 helices. The sequential breaking of the tandem hydrophobic constrictions on the M1 and S1 helices makes the two parts of the gate strictly coupled, acting as a single gate. The simulation also revealed that there is no significant energetic coupling between the inner S1 bundle and the outer M2 transmembrane helices.

show abstract

Structural Determinants of MscL Gating Studied by Molecular Dynamics Simulations

Cited by 172 publications

References 32 publications

The gating mechanism of the bacterial mechanosensitive channel MscL revealed by molecular dynamics simulations

The gating mechanism of the bacterial mechanosensitive channel MscL revealed by molecular dynamics simulations

Hydrophobic gating of mechanosensitive channel of large conductance evidenced by single-subunit resolution

Conformational pathways in the gating of Escherichia coli mechanosensitive channel

Contact Info

Product

Resources

About