Bicelle composition-dependent modulation of phospholipid dynamics by apelin peptides.

Apelin peptides are cognate ligands for the apelin receptor, a G-protein coupled receptor (GPCR). The apelinergic system plays critical roles in wide-ranging physiological activities including function and development of the central nervous and cardiovascular systems. Apelin is found in 13-55 residue isoforms in vivo, all of which share the C-terminal portion of the preproapelin precursor. Characterization of high-resolution structures and detergent micelle interactions of apelin-17 led to a two-step membrane-catalyzed binding and GPCR activation mechanism hypothesis recapitulated in longer isoforms. Here, we examine interactions of the apelin-13 and -17 isoforms with isotropic zwitterionic and mixed zwitterionic-anionic lipid bicelles to test for hallmarks of membrane catalysis in a more physiological membrane-mimetic environment than a micelle. Specifically, ¹H and ³¹P relaxation and diffusion solution-state NMR techniques demonstrate that both apelin isoforms interact with both types of isotropic bicelles. Bicelle hydrodynamics were observed to be differentially modulated by apelin peptides, although these effects were minimal. Phospholipid headgroup ³¹P spin relaxation behaviour was, conversely, clearly perturbed. Perturbation of this nature was also observed in magnetically-aligned bicelles by ³¹P solid-state NMR spectroscopy and spin relaxation experiments. This behaviour is consistent with an apelin-bicelle binding process allowing significant peptide mobility, facilitating membrane-catalyzed GPCR encounter.