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Biophys. J. BioFAST: First Published December 30, 2005. doi:10.1529/biophysj.105.070078
© 2005 by the Biophysical Society.

A more recent version of this article appeared on March 15, 2006.
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SUPRAMOLECULAR ASSEMBLIES

Redesigning Channel-Forming Peptides: Amino Acid Substitutions that Enhance Rates of Supramolecular Self-Assembly and Raise Ion Transport Activity

Lalida P. Shank 1, James R. Broughman 1, Wade Takeguchi 1, Gabe A. Cook 1, Ashley Robbins 1, Lindsey Hahn 1, Gary Radke 1, Takeo Iwamoto 1, Bruce D. Schultz 1 and John M. Tomich 1*

1 Kansas State University

* To whom correspondence should be addressed. E-mail: jtomich{at}ksu.edu.

Submitted on July 5, 2005
Revised on August 10, 2005
Accepted on 9 December 2005


  Abstract
Three series of 22-residue peptides derived from the transmembrane M2 segment of the glycine receptor {alpha}1-subunit (M2GlyR) have been designed, synthesized and tested to determine the plasticity of a channel forming sequence and to define whether channel pores with enhanced conductive properties could be created. Sixteen sequences were examined for aqueous solubility, solution-association tendency, secondary structure, half-maximal concentration for supramolecular assembly, channel activity and ion transport properties across epithelial monolayers. All peptides interact strongly with membranes: associating with, inserting across and assembling to form homo-oligomeric bundles when in micromolar concentrations. Single and double amino acid replacements involving arginine and/or aromatic amino acids within the final five C-terminal residues of the peptide cause dramatic effects on the concentration dependence, yielding a range of K1/2 values from 36 ± 5 to 390 ± 220 µM for transport activity. New water/lipid interfacial boundaries were established for the transmembrane segment using charged or aromatic amino acids, thus limiting the peptides' ability to move perpendicularly to the plane of the bilayer. Formation of discrete water/lipid interfacial boundaries appears to be necessary for efficient supramolecular assembly and high anion transport activity. A peptide sequence is identified that may show efficacy in channel replacement therapy for channelopathies such as cystic fibrosis.

Key Words: channel-forming peptide, glycine receptor, ion transport, solution associations, supermolecular assembly, transmembrane peptide




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[Abstract] [Full Text] [PDF]


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Copyright © 2005 by the Biophysical Society.