Membrane catalysis of peptide-receptor binding

Abstract

The membrane catalysis hypothesis states that a peptide ligand activates its target receptor after an initial interaction with the surrounding membrane. Upon membrane binding and interaction, the ligand is structured such that receptor binding and activation is encouraged. As evidence for this hypothesis, there are numerous studies concerning the conformation that peptides adopt in membrane mimetic environments. This mini-review analyzes the features of ligand peptides with an available high-resolution membrane-induced structure and a characterized membrane-binding region. At the peptide-membrane interface, both amphipathic helices and turn structures are commonly formed in peptide ligands and both hydrophobic and electrostatic interactions can be responsible for membrane binding. Apelin is the ligand to the G-protein coupled receptor (GPCR) named APJ, with various important physiological effects, which we have recently characterized both in solution and bound to anionic micelles. The structural changes that apelin undergoes when binding to micelles provide strong evidence for membrane catalysis of apelin-APJ interactions.

Fig. 1

Superposed structures of the peptides listed in Table 1. Where possible, all members of an ensemble have been superposed over the converged regions (Table 1) using LSQKAB (Collaborative Computational Project 1994). Backbone atoms are shown in black and the side chains of residues which are implicated in membrane-binding are blue, whenever the NMR ensemble was well superposed. (Produced using PyMOL (Delano Scientific, San Carlos, CA).)

Fig. 2

Superposed structures of apelin-17 in solution at 35°C (Langelaan et al. 2009) and in the SDS micelle-bound state (Langelaan and Rainey 2009). All 80 members of the apelin-17 structural ensemble in solution (BMRB entry 20029) are superposed over the reasonably structurally converged regions of K1-R4 and R6-L9. The 80 members of the apelin-17 structural ensemble bound to SDS micelles (BMRB entry 20082) are superimposed over backbone atoms R6-K12 and all heavy atoms from M15-F17 using LSQKAB (Collaborative Computational Project 1994). Backbone atoms are shown in black, side chains of residues involved with membrane binding in blue and the converged region at the C-terminal region of apelin-17 in red. (Produced using PyMOL (Delano Scientific, San Carlos, CA).)