Bioactivity of the putative apelin proprotein expands the repertoire of apelin receptor ligands

Publication date: Available online 22 May 2017
Source:Biochimica et Biophysica Acta (BBA) - General Subjects
Author(s): Kyungsoo Shin, Nigel A. Chapman, Muzaddid Sarker, Calem A. Kenward, Shuya K. Huang, Nathan Weatherbee-Martin, Aditya Pandey, Denis J. Dupré, Jan K. Rainey
BackgroundApelin is a peptide ligand for a class A G-protein coupled receptor called the apelin receptor (AR or APJ) that regulates angiogenesis, the adipoinsular axis, and cardiovascular functions. Apelin has been shown to be bioactive as 13, 17, and 36 amino acid isoforms, C-terminal fragments of the putatively inactive 55-residue proprotein (proapelin or apelin-55). Although intracellular proprotein processing has been proposed, isolation of apelin-55 from colostrum demonstrates potential for secretion prior to processing and the possibility of proapelin-AR interaction.MethodsApelin isoform activity and potency were compared by an In-Cell Western™ assay for ERK phosphorylation using a stably AR-transfected HEK293A cell line. Conformational comparison of apelin isoforms was carried out by cicrular dichroism and heteronuclear solution-state nuclear magnetic resonance spectroscopy.ResultsApelin-55 is shown to activate the AR, with similar maximum ERK phophorylation response and potency to the shorter isoforms except for apelin-13, which exhibited a greater potency. Correlating to this shared activity, highly similar conformations are exhibited in all apelin isoforms for the shared C-terminal region responsible for receptor binding and activation.ConclusionsAR activation by all apelin isoforms likely hinges upon shared conformation and dynamics in the C-terminus, with apelin-55 providing an alternative bioactive isoform despite the addition of 19N-terminal residues relative to apelin-36.General significanceBeyond providing novel insight into the physiology of this system, re-annotation of proapelin to the bioactive apelin-55 isoform adds to the molecular toolkit for dissection of apelin-AR interactions and expands the repertoire of therapeutic targets for the apelinergic system.



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