IMR Press / FBL / Volume 19 / Issue 7 / DOI: 10.2741/4270

Frontiers in Bioscience-Landmark (FBL) is published by IMR Press from Volume 26 Issue 5 (2021). Previous articles were published by another publisher on a subscription basis, and they are hosted by IMR Press on imrpress.com as a courtesy and upon agreement with Frontiers in Bioscience.

Open Access Article
Carboxylation-dependent conformational changes of human osteocalcin
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1 CRS4, Biomedicine sector, Parco Polaris, 09010 Pula (CA), Italy
2 Laboratory of Protein Chemistry, Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy
3 Department of Molecular Medicine and Centre for Human Reproduction Pathology, University of Padova, 35121 Padova, Italy
4 Department of Human Anatomy and Physiology, University of Padova, 35121 Padova, Italy
5 Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy
6 EURAC Institute of Mountain Emergency Medicine, 39100 Bozen/Bolzano, Italy
Front. Biosci. (Landmark Ed) 2014, 19(7), 1105–1116; https://doi.org/10.2741/4270
Published: 1 June 2014
Abstract

Osteocalcin (OCN) is a small noncollagenous protein mainly produced by osteoblasts and is highly represented in bones of most vertebrates. Human OCN contains up to three gamma-carboxyglutamic acid (Gla-OCN) residues at positions 17, 21 and 24 which are thought to increase calcium binding strength, improving mechanical properties of the bone matrix. Recent studies revealed that OCN exerts also important endocrine functions, affecting energy metabolism and male fertility. The latter effect seems to be mediated by the uncarboxylated form of OCN (Glu-OCN). We employed human and mouse OCN as models of fully carboxylated and uncarboxylated OCN forms to investigate, by the use of circular dichroism and molecular dynamics simulations, the respective conformational properties and Ca2+ affinity. Ca2+ binding was found to trigger a similar conformational transition in both Glu-OCN and Gla-OCN, from a disordered structure to a more compact/stable form. Notably, gamma-carboxylation increases the affinity of OCN for Ca2+ by > 30 fold suggesting that, in physiological conditions, Gla-OCN is essentially Ca2+-bound, whereas Glu-OCN circulates mainly in the Ca2+-free form.

Keywords
Osteocalcin
Calcium Metabolism
GammaCarboxylation
Circular Dichroism
Protein Stability
Calcium-Binding Proteins
Molecular Dynamics
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