Kassaar, Omar, Schwarz-Linek, Ulrich, Blindauer, Claudia A. and Stewart, Alan J. (2015) Plasma free fatty acid levels influence Zn2+-dependent histidine-rich glycoprotein-heparin interactions via an allosteric switch on serum albumin. Journal of Thrombosis and Haemostasis, 13 (1). pp. 101-110. doi:10.1111/jth.12771 ISSN 1538-7933.

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Abstract

Background:
Histidine-rich glycoprotein (HRG) regulates coagulation through its ability to bind and neutralize heparins. HRG associates with Zn2+ to stimulate HRG–heparin complex formation. Under normal conditions, the majority of plasma Zn2+ associates with human serum albumin (HSA). However, free fatty acids (FFAs) allosterically disrupt Zn2+ binding to HSA. Thus, high levels of circulating FFAs, as are associated with diabetes, obesity, and cancer, may increase the proportion of plasma Zn2+ associated with HRG, contributing to an increased risk of thrombotic disease.

Objectives:
To characterize Zn2+ binding by HRG, examine the influence that FFAs have on Zn2+ binding by HSA, and establish whether FFA-mediated displacement of Zn2+ from HSA may influence HRG–heparin complex formation.

Methods:
Zn2+ binding to HRG and to HSA in the presence of different FFA (myristate) concentrations were examined by isothermal titration calorimetry (ITC) and the formation of HRG–heparin complexes in the presence of different Zn2+ concentrations by both ITC and ELISA.

Results and conclusions:
We found that HRG possesses 10 Zn2+ sites (K′ = 1.63 × 105) and that cumulative binding of FFA to HSA perturbed its ability to bind Zn2+. Also Zn2+ binding was shown to increase the affinity with which HRG interacts with unfractionated heparins, but had no effect on its interaction with low molecular weight heparin (~ 6850 Da). [Correction added on 1 December 2014, after first online publication: In the preceding sentence, “6850 kDa” was corrected to “6850 Da”.] Speciation modeling of plasma Zn2+ based on the data obtained suggests that FFA-mediated displacement of Zn2+ from serum albumin would be likely to contribute to the development of thrombotic complications in individuals with high plasma FFA levels.

Item Type:	Journal Article
Subjects:	Q Science > QD Chemistry Q Science > QR Microbiology
Divisions:	Faculty of Science, Engineering and Medicine > Science > Chemistry
Library of Congress Subject Headings (LCSH):	Fatty acids, Heparin, Glycoproteins, Albumins
Journal or Publication Title:	Journal of Thrombosis and Haemostasis
Publisher:	Wiley-Blackwell Publishing Ltd.
ISSN:	1538-7933
Official Date:	13 January 2015
Dates:	Date Event 13 January 2015 Published 29 October 2014 Available 21 October 2014 Accepted 25 September 2014 Submitted
Volume:	13
Number:	1
Number of Pages:	10
Page Range:	pp. 101-110
DOI:	10.1111/jth.12771
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Open Access (Creative Commons)
Date of first compliant deposit:	28 January 2016
Date of first compliant Open Access:	28 January 2016
Funder:	British Heart Foundation, Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC)
Grant number:	FS/10/036/28352 (BHF), BB/J006467/1 (BBSRC)
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