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Biophys. J. BioFAST: First Published June 15, 2007. doi:10.1529/biophysj.107.112375
© 2007 by the Biophysical Society.

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BIOPHYSICAL LETTERS

Is Lipid Bilayer Binding a Common Property of Inhibitor Cysteine Knot Ion-Channel Blockers?

Yevgen O. Posokhov 1, Philip A. Gottlieb 2, Michael J. Morales 2, Frederick Sachs 2 and Alexey S. Ladokhin 1*

1 University of Kansas Medical Center
2 SUNY at Buffalo

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

Submitted on May 9, 2007
Revised on June 6, 2007
Accepted on 7 June 2007


  Abstract
Recent studies of several inhibitor cysteine knot (ICK) ion-channel blockers suggest that lipid bilayer interactions play a prominent role in their actions (1-3). Structural similarities led to the hypothesis that bilayer interactions are important for the entire ICK family. We have tested this hypothesis by performing direct measurements of the free energy of bilayer partitioning ({Delta}G) of several peptide blockers using our novel quenching-enhanced fluorescence titration protocol (4). We show that various ICK peptides demonstrate markedly different modes of interaction with large unilamelar lipid vesicles. The mechanosensitive channel blocker, GsMTx4, and it's active diastereomeric analogue, D-GsMTx4, bind strongly to both anionic and zwitterionic membranes. One potassium channel gating modifier, rHpTx2gs, interacts negligibly with both types of vesicles at physiological pH, while another, SGTx1, interacts only with anionic lipids. The slope of {Delta}G dependence on surface potential is very shallow for both GsMTx4 and D-GsMTx4, indicating complex interplay of their hydrophobic and electrostatic interactions with lipid. In contrast, a cell-volume regulator, GsMTx1, and SGTx1 exhibit a very steep {Delta}G dependence on surface potential, resulting in a strong binding only for membranes rich in anionic lipids. The high variability of 5 kcal/mole in observed {Delta}G shows that bilayer partitioning is not a universal property of the ICK peptides interacting with ion channels


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Copyright © 2007 by the Biophysical Society.