The Anti-angiogenic His/Pro-rich Fragment of Histidine-rich Glycoprotein Binds to Endothelial Cell Heparan Sulfate in a Zn2+-dependent Manner
2006 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 281, no 15, 10298-10304 p.Article in journal (Refereed) Published
The plasma protein histidine-rich glycoprotein (HRGP), which has been identified as an angiogenesis inhibitor, binds to heparan sulfate (HS) in a Zn2+-dependent manner. We wished to test whether this interaction is mechanistically important in mediation of the anti-angiogenic effect of HRGP. Inhibition of angiogenesis by HRGP is exerted through its central His/Pro-rich domain, which is proteolytically released. A 35-amino-acid residue synthetic peptide, HRGP330, derived from the His/Pro-rich domain retains the inhibitory effect on blood vessel formation in vitro and in vivo, an effect dependent on the presence of Zn2+. We now show that HRGP330 binds heparin/HS with the same capacity as full-length HRGP, and the binding is Zn2+-dependent. Peptides derived from the His/Pro-rich domain of HRGP downstream of HRGP330 fail to inhibit endothelial cell migration and display a significantly reduced heparin-binding capacity. An even shorter peptide, HRGP335, covering a 26-amino-acid sequence within HRGP330 retains full heparin/HS-binding capacity. Characterization of the HS interaction shows that there is a tissue-specific HS pattern recognized by HRGP335 and that the minimal length of heparin/HS required for binding to HRGP335 is an 8-mer oligosaccharide. Saturation of the HS binding sites in HRGP330 by pre-incubation with heparin abrogates the HRGP330-induced rearrangement of endothelial cell focal adhesions, suggesting that interactio
Place, publisher, year, edition, pages
2006. Vol. 281, no 15, 10298-10304 p.
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-94162DOI: 10.1074/jbc.M508483200PubMedID: 16436387OAI: oai:DiVA.org:uu-94162DiVA: diva2:167917
De två första författarna delar första författarskapet.2006-03-302006-03-302013-03-21Bibliographically approved