Journal
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
Volume 1861, Issue 8, Pages 1901-1912Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbagen.2017.05.017
Keywords
Apelin (APLN); Apelin receptor (APJ APLNR); Proprotein; In-Cell Western assay; NMR spectroscopy; CD spectropolarimetry
Categories
Funding
- Canadian Institutes of Health Research (CIHR) [MOP-111138]
- Nova Scotia Health Research Foundation (NSHRF) [MED-SSG-2015-10041]
- Strategic Cooperative Education Initiative - Nova Scotia Economic and Rural Development and Tourism
- Natural Sciences and Engineering Research Council of Canada (NSERC) [RGPIN-355310-2013]
- Canadian Foundation for Innovation
- NSERC
- Dalhousie Medical Research Foundation
- Atlantic Canada Opportunities Agency Grant
- NSERC Alexander Graham Bell Canadian Graduate Scholarship
- NSERC Undergraduate Student Research Award
- Beatrice Hunter Cancer Research Institute
- Canadian Imperial Bank of Commerce
- CIHR New Investigator Award
- Harvey Graham Cancer Research Fund as part of Terry Fox Strategic Health Research Training Program in Cancer Research at CIHR
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Background: Apelin 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 and milk demonstrates potential for secretion prior to processing and the possibility of proapelin-AR interaction. Methods: Apelin isoform activity and potency were compared by an In-Cell Western (TM) assay for ERK phosphorylation using a stably AR-transfected HEK293A cell line. Conformational comparison of apelin isoforms was carried out by circular dichroism and heteronuclear solution-state nuclear magnetic resonance spectroscopy. Results: Apelin-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. Conclusions: AR 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 19 N-terminal residues relative to apelin-36.
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