Mammalian histidine-rich glycoprotein (HRG) is a glycosylated protein of ~70 kDa in size and is present in blood plasma at relatively high concentrations (~1.5 M). It has numerous binding partners, such as heparin, plasminogen, divalent metal ions, and heme, and is involved in many essential regulatory biological processes, including blood coagulation, cell migration, proliferation and adhesion, tumour growth inhibition and angiogenesis, as well as immune complex clearance. HRG has therefore been referred to as the "Swiss Army knife of mammalian plasma". Despite a plethora of functions, there is surprisingly little experimental evidence illuminating HRG structure. The protein exhibits a multi-domain arrangement with two N-terminal (N1 and N2) and one C-terminal (C) domain and has a central histidine-rich region (HRR) that is flanked by proline-richregions (PRRs) on either side (Figure ). While this domain structure is well established, a highresolution structure is only available for one of the two N-terminal domains (N2). The small size of HRG makes cryo-electron microscopy rather challenging, and an HRG fragment comprising the HRR and parts of both PRRs was predicted to be intrinsically disordered, which may explain the lack of available high resolution X-ray structures for the full-length protein. In fact, recent availability of AlphaFold2 (AF2) protein structure prediction in combination with JPred4 secondary structure prediction based on the full HRG sequence strongly support the idea of high disorder (in the absence of interaction partners) for the PRR1-HRR-PRR2 stretch (Figures and).