Localized apelin-17 analogue-bicelle interactions as a facilitator of membrane-catalyzed receptor recognition and binding.
Biochim Biophys Acta Biomembr
; 1866(3): 184289, 2024 Mar.
Article
em En
| MEDLINE
| ID: mdl-38278504
ABSTRACT
The apelinergic system encompasses two peptide ligand families, apelin and apela, along with the apelin receptor (AR or APJ), a class A G-protein-coupled receptor. This system has diverse physiological effects, including modulating heart contraction, vasodilation/constriction, glucose regulation, and vascular development, with involvement in a variety of pathological conditions. Apelin peptides have been previously shown to interact with and become structured upon binding to anionic micelles, consistent with a membrane-catalyzed mechanism of ligand-receptor binding. To overcome the challenges of observing nuclear magnetic resonance (NMR) spectroscopy signals of a dilute peptide in biological environments, 19F NMR spectroscopy, including diffusion ordered spectroscopy (DOSY) and saturation transfer difference (STD) experiments, was used herein to explore the membrane-interactive behaviour of apelin. NMR-optimized apelin-17 analogues with 4-trifluoromethyl-phenylalanine at various positions were designed and tested for bioactivity through ERK activation in stably-AR transfected HEK 293 T cells. Far-UV circular dichroism (CD) spectropolarimetry and 19F NMR spectroscopy were used to compare the membrane interactions of these analogues with unlabelled apelin-17 in both zwitterionic/neutral and net-negative bicelle conditions. Each analogue binds to bicelles with relatively weak affinity (i.e., in fast exchange on the NMR timescale), with preferential interactions observed at the cationic residue-rich N-terminal and mid-length regions of the peptide leaving the C-terminal end unencumbered for receptor recognition, enabling a membrane-anchored fly-casting mechanism of peptide search for the receptor. In all, this study provides further insight into the membrane-interactive behaviour of an important bioactive peptide, demonstrating interactions and biophysical behaviour that cannot be neglected in therapeutic design.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Hormônios Peptídicos
Limite:
Humans
Idioma:
En
Revista:
Biochim Biophys Acta Biomembr
Ano de publicação:
2024
Tipo de documento:
Article