Conformation and orientation of regulatory peptides on lipid membranes. Key to the molecular mechanism of receptor selection.
The reaction of regulatory peptides with their membrane-bound receptors often occurs via a membrane-associated state of the peptide. From infrared studies on thin lipid films, we have shown that several ligands of the opioid kappa receptor and the neurokinin NK-1 receptor insert their message segments as an alpha-helix, more or less perpendicularly, into the membrane. The binding parameters for these membrane-associated states were determined from the capacitance minimization potential of lipid bilayers. A theory has been developed to account for the observed binding constants and the preferred conformation and orientation of these peptides. In contrast to the kappa and NK-1 receptors, ligands of the opioid mu and delta, and the neurokinin NK-2 and NK-3 receptors, are predicted not to form the inserted alpha-helical structure. A selection between the mu and delta (or NK-2 and NK-3) receptors appears to be made on the basis of an electrostatic gradient near the membrane surface. The molecular mechanism of receptor selection thus appears to be based to a large extent on the membrane-induced compartmentalization of ligands for the different receptors.
Sargent
D F
DF
Institute of Molecular Biology and Biophysics, Swiss Federal Institute of Technology, Zürich, Switzerland.
Bean
J W
JW
Schwyzer
R
R
D006728:Hormones / Q000378:metabolism*; D008433:Mathematics; D008566:Membranes / Q000378:metabolism; D008962:Models, Theoretical; D010455:Peptides / Q000378:metabolism*; D011487:Protein Conformation; D011956:Receptors, Cell Surface / Q000378:metabolism*
D006728:Hormones; D010455:Peptides; D011956:Receptors, Cell Surface