Mechanosensitive channels: what can we learn from ‘simple’ model systems?

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Abstract

Mechanosensitive ion channels, which convert external mechanical forces into electrical and chemical signals in cells, are diverse. Presently, there is no known common sequence ‘signature’ that identifies mechanosensitivity. Bacterial mechanosensitive channels gated by membrane tension represent convenient models allowing us to combine structural information with the insights gained from biophysical analysis, biochemistry, genetic screens, bacterial physiology and molecular computation. Here, the conformational transition driven by membrane tension in the bacterial channel MscL is discussed. The predicted pathway suggests roles for distinct protein domains, surrounding lipids and water in the gating process. MscL, a simple system, thus helps us obtain a coherent picture of molecular events, and build concepts and strategies that can be applied to more elaborate mechanosensory systems in the near future.

Section snippets

Functional diversity

The structural diversity of mechanosensitive channels seems to have come from the physiological necessity to detect pressures ranging by at least eight orders of magnitude – roughly from 10−4 to 104 N m−2, which can be taken as characteristic measures of a faint sound and aortic pressure, respectively. The mechanosensory transduction in vertebrate auditory hair cells is the best example of a fast-acting mechanism where the pressure of a sound wave is focused on the putative channel gate via inner

The families

Genetic screens in model organisms such as nematodes, flies, zebrafish and mice have identified several genes encoding channel-like molecules involved in mechanosensory responses 9, 10, 11, 12. The channels thus identified are provisionally called mechanosensitive and, in the absence of reconstitution data, the evidence regarding their exact mode of action remains largely circumstantial. Several types of K+ channels were found to be strongly mechanically modulated 13, 14, 15, 16. Biochemical

Force is not a ligand

It appears that mechanoreceptors arose independently several times in the course of evolution. Each time, the problem of gauging a specific force was solved differently by recruiting a member from an existing family of channels. Peculiarly, families that include mechanosensitive channels also contain many members that are non-mechanosensitive, emphasizing sub-specialization and high evolvability within the families themselves. Indeed, mechanical force is different from a ligand, to which a

The gates swing

What is special about mechanosensitive channel gating? As small molecular machines, all gated ion channels consume energy from an external stimulus that helps them to switch from the non-conducting to the conducting state. The energy of the stimulus in each particular case is received either by a voltage sensor interacting with the electric field [30], from the interaction of the ligand-binding pocket with a ligand [31], or as the work of an external mechanical force destabilizing the resting

Bacteria feel and evade osmotic stress

Bacterial mechanosensitive channels were first reported in 1987 when the patch-clamp technique was successfully applied to bacterial spheroplasts [38]. At least two types of activities were discerned in E. coli preparations [39]. These were named MscL and MscS, for their large (3.2 nS) and small (∼1.0 nS) conductances, respectively. The channels were soon recognized as components of the osmolyte efflux system activated under hypo-osmotic shock. The protein-forming large-conductance channel MscL

MscL structure

E. coli MscL (EcoMscL) consists of five identical subunits, each 136 amino acids long. Each subunit crosses the membrane twice through α-helical transmembrane segments, M1 and M2, interconnected by an extracellular (periplasmic) loop. The model of EcoMscL in its closed conformation, built by homology to the crystal structure of TbMscL [44], is shown in Figure 2 (left). TbMscL N-terminal S1 domains were not resolved in the crystal structure. The N-terminal domains (red in Figure 2) were inferred

Concluding remarks

It should be noted that although MscL is a typical bacterial channel with no close eukaryotic homologs [26], it is to date the best-understood mechanosensitive channel. Its unique structure and mechanism of gating do not permit direct replication beyond the group of its bacterial orthologs. Instead of being a prototype for sequence-based or structure-based generalizations, MscL offers a powerful system for studying basic principles of tension-driven conformational transitions in membrane

Acknowledgements

Work in the Sukharev laboratory is supported by NASA and NIH. We acknowledge critical contribution from H.R. Guy (NIH, Bethesda) in building MscL models.

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