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J. Biol. Chem., Vol. 278, Issue 23, 21076-21082, June 6, 2003

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Generation and Evaluation of a Large Mutational Library from the Escherichia coli Mechanosensitive Channel of Large Conductance, MscL

IMPLICATIONS FOR CHANNEL GATING AND EVOLUTIONARY DESIGN^*,\

Joshua A. Maurer  and Dennis A. Dougherty 

From the Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125

Random mutagenesis of the mechanosensitive channel of large conductance (MscL) from Escherichia coli coupled with a high-throughput functional screen has provided new insights into channel structure and function. Complementary interactions of conserved residues proposed in a computational model for gating have been evaluated, and important functional regions of the channel have been identified. Mutational analysis shows that the proposed S1 helix, despite having several highly conserved residues, can be heavily mutated without significantly altering channel function. The pattern of mutations that make MscL more difficult to gate suggests that MscL senses tension with residues located near the lipid headgroups of the bilayer. The range of phenotypical changes seen has implications for a proposed model for the evolutionary origin of mechanosensitive channels.

Received for publication, March 21, 2003 , and in revised form, April 1, 2003.

^* This work was supported by National Institutes of Heath Program Project Grant GM-62532. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains two supplementary tables.

Recipient of National Institutes of Health Predoctoral Trainee Grant GM-08501.

To whom correspondence should be addressed: Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 E. California Blvd., Mail Code 164-30 Cr, Pasadena, CA 91125. Tel.: 626-395-6089; Fax: 626-564-9297; E-mail: dad{at}igor.caltech.edu.

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