Abstract
Adiponectin, a hormone secreted from adipocytes, has been shown to protect against development of insulin resistance, ischemia–reperfusion injury, and inflammation. Adiponectin assembles into multiple oligomeric isoforms: trimers, hexamers and several higher molecular weight (HMW) species. Of these, the HMW species are selectively decreased during the onset of type 2 diabetes. Despite the critical role of HMW adiponectin in insulin responsiveness, its assembly process is poorly understood. In this report, we investigated the role of divalent cations in adiponectin assembly. Purified adiponectin 18mers, the largest HMW species, did not collapse to smaller oligomers after treatment with high concentrations of EDTA. However, treatment with EDTA or another chelator DTPA inhibited the oligomerization of 18mers from trimers in vitro. Zn2+ specifically increased the formation of 18mers when compared with Cu2+, Mg2+, and Ca2+. Distribution of adiponectin oligomers secreted from zinc chelator TPEN-treated rat adipocytes skewed toward increased proportions of hexamers and trimers. While we observed presence of zinc in adiponectin purified from calf serum, the role of zinc in disulfide bonding between oligomers was examined because the process is critical for 18mer assembly. Surprisingly, Zn2+ inhibited disulfide bond formation early in the oligomerization process. We hypothesize that initial decreases in disulfide formation rates could allow adiponectin subunits to associate before becoming locked in fully oxidized conformations incapable of further oligomerization. These data demonstrate that zinc stimulates oligomerization of HMW adiponectin and possibly other disulfide-dependent protein assembly processes.
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Acknowledgments
We thank Drs. Vicki Wysocki, Vahe Bandarian, Megan McEvoy, and Lisa Rezende for valuable discussions throughout this study. This work is supported by Junior Faculty Award from the American Diabetes Association (1-08-JF-54) and by a grant from the Arizona Biomedical Research Commission to T.-S.T. D.B.B. is a recipient of a graduate training grant in biochemistry and molecular and cellular biology (GM08659). ICP-MS and analytical centrifugation analyses were performed in, respectively, the Arizona Laboratory for Emerging Contaminants and the Analytical Biophysics and Materials Characterization Facility at University of Arizona Department of Chemistry and Biochemistry.
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Briggs, D.B., Giron, R.M., Schnittker, K. et al. Zinc enhances adiponectin oligomerization to octadecamers but decreases the rate of disulfide bond formation. Biometals 25, 469–486 (2012). https://doi.org/10.1007/s10534-012-9519-9
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DOI: https://doi.org/10.1007/s10534-012-9519-9