Divalent metal binding by histidine-rich glycoprotein differentially regulates higher order oligomerisation and proteolytic processing

Abstract

The serum protein histidine-rich glycoprotein (HRG) has been implicated in tissue injury and tumour growth. Several HRG functions are regulated by the divalent metal Zn²⁺ , including ligand binding and proteolytic processing that releases active HRG fragments. Although HRG can bind divalent metals other than Zn²⁺ , the impact of these divalent metals on the biophysical properties of HRG remains poorly understood. We now show that HRG binds Zn²⁺ , Ni²⁺ , Cu²⁺ and Co²⁺ with micromolar affinities, but differing stoichiometries, and regulate the release of specific HRG fragments during proteolysis. Furthermore, HRG binding to Zn²⁺ promotes HRG dimer formation in a Zn²⁺ -concentration- and pH-dependent manner. Our data highlight the complex divalent metal-dependent regulatory mechanisms that govern HRG function.

Keywords: divalent metals; histidine-rich glycoprotein; zinc.