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Binding of the human antioxidation protein α1-microglobulin (A1M) to heparin and heparan sulfate. Mapping of binding site, molecular and functional characterization, and co-localization in vivo and in vitro

Bergwik, Jesper LU ; Kristiansson, Amanda LU ; Larsson, Jörgen LU ; Ekström, Simon LU ; Åkerström, Bo LU and Allhorn, Maria LU (2021) In Redox Biology 41.
Abstract

Heparin and heparan sulfate (HS) are linear sulfated disaccharide polymers. Heparin is found mainly in mast cells, while heparan sulfate is found in connective tissue, extracellular matrix and on cell membranes in most tissues. α1-microglobulin (A1M) is a ubiquitous protein with thiol-dependent antioxidant properties, protecting cells and matrix against oxidative damage due to its reductase activities and radical- and heme-binding properties. In this work, it was shown that A1M binds to heparin and HS and can be purified from human plasma by heparin affinity chromatography and size exclusion chromatography. The binding strength is inversely dependent of salt concentration and proportional to the degree of sulfation of heparin... (More)

Heparin and heparan sulfate (HS) are linear sulfated disaccharide polymers. Heparin is found mainly in mast cells, while heparan sulfate is found in connective tissue, extracellular matrix and on cell membranes in most tissues. α1-microglobulin (A1M) is a ubiquitous protein with thiol-dependent antioxidant properties, protecting cells and matrix against oxidative damage due to its reductase activities and radical- and heme-binding properties. In this work, it was shown that A1M binds to heparin and HS and can be purified from human plasma by heparin affinity chromatography and size exclusion chromatography. The binding strength is inversely dependent of salt concentration and proportional to the degree of sulfation of heparin and HS. Potential heparin binding sites, located on the outside of the barrel-shaped A1M molecule, were determined using hydrogen deuterium exchange mass spectrometry (HDX-MS). Immunostaining of endothelial cells revealed pericellular co-localization of A1M and HS and the staining of A1M was almost completely abolished after treatment with heparinase. A1M and HS were also found to be co-localized in vivo in the lungs, aorta, kidneys and skin of mice. The redox-active thiol group of A1M was unaffected by the binding to HS, and the cell protection and heme-binding abilities of A1M were slightly affected. The discovery of the binding of A1M to heparin and HS provides new insights into the biological role of A1M and represents the basis for a novel method for purification of A1M from plasma.

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author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
GAG, Heparan sulfate, Heparin, Heparin binding protein, Oxidative stress, α-microglobulin
in
Redox Biology
volume
41
article number
101892
publisher
Elsevier
external identifiers
  • pmid:33607500
  • scopus:85102856567
ISSN
2213-2317
DOI
10.1016/j.redox.2021.101892
language
English
LU publication?
yes
id
c48015e5-707d-42c9-b696-f8d4685000c8
date added to LUP
2021-03-30 12:25:30
date last changed
2024-06-29 10:02:31
@article{c48015e5-707d-42c9-b696-f8d4685000c8,
  abstract     = {{<p>Heparin and heparan sulfate (HS) are linear sulfated disaccharide polymers. Heparin is found mainly in mast cells, while heparan sulfate is found in connective tissue, extracellular matrix and on cell membranes in most tissues. α<sub>1</sub>-microglobulin (A1M) is a ubiquitous protein with thiol-dependent antioxidant properties, protecting cells and matrix against oxidative damage due to its reductase activities and radical- and heme-binding properties. In this work, it was shown that A1M binds to heparin and HS and can be purified from human plasma by heparin affinity chromatography and size exclusion chromatography. The binding strength is inversely dependent of salt concentration and proportional to the degree of sulfation of heparin and HS. Potential heparin binding sites, located on the outside of the barrel-shaped A1M molecule, were determined using hydrogen deuterium exchange mass spectrometry (HDX-MS). Immunostaining of endothelial cells revealed pericellular co-localization of A1M and HS and the staining of A1M was almost completely abolished after treatment with heparinase. A1M and HS were also found to be co-localized in vivo in the lungs, aorta, kidneys and skin of mice. The redox-active thiol group of A1M was unaffected by the binding to HS, and the cell protection and heme-binding abilities of A1M were slightly affected. The discovery of the binding of A1M to heparin and HS provides new insights into the biological role of A1M and represents the basis for a novel method for purification of A1M from plasma.</p>}},
  author       = {{Bergwik, Jesper and Kristiansson, Amanda and Larsson, Jörgen and Ekström, Simon and Åkerström, Bo and Allhorn, Maria}},
  issn         = {{2213-2317}},
  keywords     = {{GAG; Heparan sulfate; Heparin; Heparin binding protein; Oxidative stress; α-microglobulin}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{Redox Biology}},
  title        = {{Binding of the human antioxidation protein α<sub>1</sub>-microglobulin (A1M) to heparin and heparan sulfate. Mapping of binding site, molecular and functional characterization, and co-localization in vivo and in vitro}},
  url          = {{http://dx.doi.org/10.1016/j.redox.2021.101892}},
  doi          = {{10.1016/j.redox.2021.101892}},
  volume       = {{41}},
  year         = {{2021}},
}