We hypothesize that this arrangement is key for enabling tight regulation of metal ion concentration in mammalian plasma and that the induced transient structural features lead to different affinities of HRG for interaction partners such as heparin, thus regulating and targeting HRG function. Transient free Zn II concentrations in plasma at specific sites (for example, at the surface of activated platelets) can reach very high levels locally; while it is difficult to determine exact concentrations in such transient events, it can be estimated that a molar ratio ≥30 with relative to the HRG plasma concentration is likely, and even required to induce certain functionality. This is in agreement with our findings that additional lower-affinity binding sites were occupied at high (>20 molar equivalents) Cu II load, suggesting new transient structural features upon occupation of these additional sites having a direct functional effect. One can envision that the flexible, unstructured PRR1-HRR-PRR2 region wraps around an HRG-partner complex, with the subsequent binding of metal ions locking this transient structure in place to stabilise the complex, while the known plasmin cleavage of the HRR could provide a mechanism for targeted release of metal ions.