Conformation and orientation of regulatory peptides on lipid membranes: Key to the molecular mechanism of receptor selection

• Published in: Biophysical chemistry 1988-08, Vol.31 (1), p.183-193
• Main Authors: Sargent, D.F., Bean, J.W., Schwyzer, R.
• Format: Article
• Language: English
• Subjects: Heterogeneous reaction; Hormones - metabolism; Mathematics; Membrane interaction; Membranes - metabolism; Models, Theoretical; Peptides - metabolism; Protein Conformation; Receptor selection; Receptors, Cell Surface - metabolism; Regulatory peptide; Secondary structure prediction
• ISSN: 0301-4622; 1873-4200
• DOI: 10.1016/0301-4622(88)80024-3

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 κ receptor and the neurokinin NK-1 receptor insert their message segments as an α-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 κ and NK-1 receptors, ligands of the opioids μ and δ, and the neurokinin NK-2 and NK-3 receptors, are predicted not to form the inserted α-helical structure. A selection between the μ and δ (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.