Apelinergic System Structure and Function

Abstract

Apelin and apela (ELABELA/ELA/Toddler) are two peptide ligands for a class A G-protein-coupled receptor named the apelin receptor (AR/APJ/APLNR). Ligand-AR interactions have been implicated in regulation of the adipoinsular axis, cardiovascular system, and central nervous system alongside pathological processes. Each ligand may be processed into a variety of bioactive isoforms endogenously, with apelin ranging from 13 to 55 amino acids and apela from 11 to 32, typically being cleaved C-terminal to dibasic proprotein convertase cleavage sites. The C-terminal region of the respective precursor protein is retained and is responsible for receptor binding and subsequent activation. Interestingly, both apelin and apela exhibit isoform-dependent variability in potency and efficacy under various physiological and pathological conditions, but most studies focus on a single isoform. Biophysical behavior and structural properties of apelin and apela isoforms show strong correlations with functional studies, with key motifs now well determined for apelin. Unlike its ligands, the AR has been relatively difficult to characterize by biophysical techniques, with most characterization to date being focused on effects of mutagenesis. This situation may improve following a recently reported AR crystal structure, but there are still barriers to overcome in terms of comprehensive biophysical study. In this review, we summarize the three components of the apelinergic system in terms of structure-function correlation, with a particular focus on isoform-dependent properties, underlining the potential for regulation of the system through multiple endogenous ligands and isoforms, isoform-dependent pharmacological properties, and biological membrane-mediated receptor interaction. © 2018 American Physiological Society. Compr Physiol 8:407-450, 2018.

Mixed Fluorotryptophan Substitutions at the Same Residue Expand the Versatility of 19F Protein NMR Spectroscopy

“…The AR has two known cognate peptide ligands, apelin and apela, each of which is found in multiple bioactive isoforms of varying length . The physiological effects of AR activation differ as a function both of ligand identity and of isoform size for a given ligand .…”

“…The AR has two known cognate peptide ligands, apelin and apela, each of which is found in multiple bioactive isoforms of varying length . The physiological effects of AR activation differ as a function both of ligand identity and of isoform size for a given ligand . Similarly‐sized but physicochemically and sequentially (Figure S4) distinct apelin‐36 and apela‐32 ligands (at natural abundance) were independently titrated into TM1‐3 (uniformly 15 N‐enriched, biosynthetically 5F‐ and 7F‐Trp labeled isoforms) samples in SDS micelles.…”

“…The physiological effects of AR activation differ as a function both of ligand identity and of isoform size for a given ligand . Similarly‐sized but physicochemically and sequentially (Figure S4) distinct apelin‐36 and apela‐32 ligands (at natural abundance) were independently titrated into TM1‐3 (uniformly 15 N‐enriched, biosynthetically 5F‐ and 7F‐Trp labeled isoforms) samples in SDS micelles. From previous mutagenesis studies, TM1‐3 contains residues in the N‐terminal tail and ECL1 essential for apelin binding .…”

“…In the case of apelin, modulation of local dynamics within the ECL1 segment containing W95 (Figure ) seems the most likely source of the observed decrease in W95 19 F peak intensity without local perturbation at the other proximal Trp positions. It is, thus, possible that apela and apelin bind to the AR with distinct mechanisms, corresponding to signaling differences . Further characterization of the interaction of each ligand with full‐length AR is required to definitively test for distinct binding mechanisms.…”

The Elabela-APJ axis: a promising therapeutic target for heart failure

“…The underlying mechanisms of the ELA-APJ axis remain largely unclear despite their clinical importance. Furthermore, some studies have introduced different isoforms of ELA as agonists of APJ and future medications for HF [17,18,29]. This review discusses the biological characteristics of the ELA-APJ axis, its cardioprotective effects, and its potential mechanisms for treating HF.…”