Mechanosensitive Channel of Small Conductance: More Than Just a Pretty Protein

Cartoon representation on black background colored by chain

Mechanosensitive channel proteins don’t always get the respect that they deserve. It’s easy to forget about our membrane-bound friends, but I want to bring them back into the spotlight.  First of all, their structure is incredible. Mechanosensitive channels form a cylindrical shape made up seven amino acid chains. The structure of mechanosensitive channels is separated into transmembrane and extramembrane regions. Several arginines are located within the transmembrane channel which causes the channel to be positively charged. The positive charge spanning the channel could explain why the mechanosensitive channels prefer to conduct anions rather than cations.

Spheres on white background colored by chainbows

But mechanosensitive channels of small conductance are known for more than just their good looks.  Mechanosensitive channels are important in their role in helping cells adapt to changes in external osmolarity. Applied tension in the cell membrane results in a change in orientation of certain helices which leads to a change in cross sectional area. The channel opens and tension in the cell membrane is relieved. Mechanosensitive channels are also influenced by membrane depolarization and are more likely to be found “open” under such conditions. Loss of function of mechanosensitive channels can be dangerous to an organism. In one study, researchers studied the effects of a peptide found in the venom of tarantulas. The ampiphathic peptide was able to penetrate into the plasma membrane near to the mechanosensitive channel where it then acted as a gating modifier. As mentioned previously, normally during channel opening the protein undergoes a conformational change in which it thins as it widens with the surrounding lipids in the membrane thinning as well. If the tarantula venom peptide is present nearby to the protein channel, it disturbs this process and the channel remains closed.  General anesthesia is also thought to work in a similar way to this. Researchers found that some anesthetics appear to act by incorporating themselves into the plasma membrane. This results in a change in tension in the membrane which leads to a corresponding change in the conformation of the channel protein. An anesthetic will inhibit the channel protein if the conformational change results in a greater cross sectional area in the portion nearest to the aqueous side than the area in the middle of the membrane. However, if the conformational change results in a greater cross sectional area of the channel protein in the middle of the plasma membrane then the anesthetic is going to increase the channel protein’s activity.

Spheres on black background colored by chain

References:

Bass, Randall B., Pavel Strop, Margaret Barclay, and Douglas C. Rees. "Crystal Structure of Escherichia coli MscS, a Voltage-Modulated and Mechanosensitive Channel." Science 298.5598 Nov. (2002): 1582-87.

Hurst, AC, PA Gottlieb, and B Martinac. "Concentration dependent effect of GsMTx4 on mechanosensitive channels of small conductance in E. coli spheroplasts." European Biophysics Journal 38.4 Apr. (2009): 415-25.

Cantor, Robert S. "The Lateral Pressure Profile in Membranes: A Physical Mechanism of General Anesthesia." Biochemistry36.94 Mar. (1997): 2339-44.

Steinbacher, S., R. Bass, P. Strop, and D.C. Rees. "Structures of the Prokaryotic Maechanosensitive Channels MscS." Current Topics in Membranes 58 (2007): 1-24.

A little bit more about MscS...

Crystal Structure of Escherichia coli MscS, a Voltage-Modulated and Mechanosensitive Channel

Mechanosensitive channels of small conductance are channel proteins that open in response to stretching of the cell and thus help the cell adapt to changes in external osmolarity. The channels open and close due to conformational changes in the protein structure in response to environmental signals such as applied tension. Mechanosensitive channels are also influenced by membrane depolarization and are more likely found to be “open” under such conditions. In this article, the researchers sought to examine the structure of the protein. Mechanosensitive channels have a cylindrical structure and are separated into transmembrane and extramembrane regions. Several arginines are located within the transmembrane channel and cause the channel to be positively charged. This positive charge spanning the channel could explain why the mechanosensitive channels prefer to conduct anions rather than cations. The researchers also looked at the mechanism of the opening and closing of the gate in terms of the protein’s structure. Applied tension results in a change in orientation of certain helices which leads to a change in cross sectional area. This could serve as a sensor between cell tension and conformational changes.

Bass, Randall B., Pavel Strop, Margaret Barclay, and Douglas C. Rees. "Crystal Structure of Escherichia coli MscS, a Voltage-Modulated and Mechanosensitive Channel." Science 298.5598 Nov. (2002): 1582-87.

Concentration dependent effect of GsMTx4 on mechanosensitive channels of small conductance in E. coli spheroplasts

In previous studies it has been found that amphipathic molecules induce the spontaneous closing of mechanosensitive channels of small conductance. However, the mechanisms by which they do so is not fully understood. In this study, the researchers examined the amphipathic peptide GsMTx4 which is found in the venom of tarantulas. GsMTx4 is known to be a specific inhibitor of mechanosensitive channels and the researchers hoped that study of the interactions between the protein and the channel would lead to better understanding of the mechanism by which tension in the membrane leads to structural changes in the channel. The researchers found that GsMTx4 is able to penetrate into the plasma membrane near to the mechanosensitive channel and acts as a gating modifier. The researchers believe that GsMTx4 alters the interactions between the channel protein and the membrane without direct contact with the channel protein itself. Normally during channel opening, the protein undergoes a conformational change in which it thins as it widens with the surrounding lipids in the membrane thinning as well. If GsMTx4 is present nearby to the protein channel, it will disturb this process and the channel will remain closed.

Hurst, AC, PA Gottlieb, and B Martinac. "Concentration dependent effect of GsMTx4 on mechanosensitive channels of small conductance in E. coli spheroplasts." European Biophysics Journal 38.4 Apr. (2009): 415-25. Print.

The Lateral Pressure Profile in Membranes: A Physical Mechanism of General

Anesthesia

This paper suggests that general anesthesia works through the inhibition of protein channels such as the mechanosensitive channel of small conductance. The researchers found that some anesthetics appear to act by incorporating itself into the plasma membrane which results in a change in tension in the membrane. This change in tension in the membrane then leads to a corresponding change in the conformation of the channel protein. An anesthetic will inhibit the channel protein if the conformational change results in a greater cross sectional area in the portion nearest to the aqueous side than the area in the middle of the membrane. However, if the conformational change results in a greater area cross sectional area of the channel protein in the middle of the plasma membrane then the anesthetic is going to increase the channel protein’s activity. 

Cantor, Robert S. "The Lateral Pressure Profile in Membranes: A Physical Mechanism of General Anesthesia." Biochemistry36.94 Mar. (1997): 2339-44.

Visual Representations of Mechanosensitive Channel of Small Conductance

                                    
                     Cartoon representation on black background colored by chain

Spheres on white background colored by chainbows (end view)

 Cartoon on light gray background colored by chain (end view)

               Line representation on white background colored by spectrum b-factors

 Surface representation on gray background colored by secondary structure