title: 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.
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia.
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Priebatsch
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia.
authors.forename: Ivan K H
authors.initials: IK
authors.lastname: Poon
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia.
authors.forename: Kruti K
authors.initials: KK
authors.lastname: Patel
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia.
authors.forename: Marc
authors.initials: M
authors.lastname: Kvansakul
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Hulett
mesh_terms: D002151:Calorimetry; D002850:Chromatography, Gel; D006801:Humans; D006863:Hydrogen-Ion Concentration; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D059748:Proteolysis; D013054:Spectrophotometry, Atomic; D014357:Trypsin / Q000378:metabolism; D015032:Zinc / Q000378:metabolism*; D000099053:Histidine-Rich Glycoprotein
chemical_list: D011506:Proteins; D000099053:Histidine-Rich Glycoprotein; D014357:Trypsin; D015032:Zinc
keywords: divalent metals; histidine-rich glycoprotein; zinc