Journal
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
Volume 1818, Issue 4, Pages 1039-1048Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbamem.2011.07.037
Keywords
Channel-forming peptide; Self-assembly; Glycine receptor; Pore structure
Categories
Funding
- PHS-NIH [RO1 074096]
- Terry Johnson Cancer Center
- Division Of Computer and Network Systems
- Direct For Computer & Info Scie & Enginr [1126709] Funding Source: National Science Foundation
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The design, synthesis, modeling and in vitro testing of channel-forming peptides derived from the cys-loop superfamily of ligand-gated ion channels are part of an ongoing research focus. Over 300 different sequences have been prepared based on the M2 transmembrane segment of the spinal cord glycine receptor alpha-subunit A number of these sequences are water-soluble monomers that readily insert into biological membranes where they undergo supramolecular assembly, yielding channels with a range of selectivities and conductances. Selection of a sequence for further modifications to yield an optimal lead compound came down to a few key biophysical properties: low solution concentrations that yield channel activity, greater ensemble conductance, and enhanced ion selectivity. The sequence NK4-M2GlyR T19R, S22W (KKKKPARVGL-GITVLTMRTQW) addressed these criteria. The structure of this peptide has been analyzed by solution NMR as a monomer in detergent micelles, simulated as five-helix bundles in a membrane environment, modified by cysteine-scanning and studied for insertion efficiency in liposomes of selected lipid compositions. Taken together, these results define the structural and key biophysical properties of this sequence in a membrane. This model provides an initial scaffold from which rational substitutions can be proposed and tested to modulate anion selectivity. This article is part of a Special Issue entitled: Protein Folding in Membranes. (C) 2011 Elsevier B.V. All rights reserved.
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