A. The effect of transition metals on the binding of HPRG was investigated next.

Question

A. The effect of transition metals on the binding of HPRG was investigated next. The ability of increasing concentrations of Cu2+ and Zn2+ to promote HPRG binding to heparin at pH = 7.3 was measured. The results are shown in Figure A2. In addition, the binding of HPRG to heparin in the presence of these ions was compared at various pHs. Figure 2.4 shows the comparison of binding of various concentrations of zinc ions at pH values ranging from 6.0 to 7.4. What is your interpretation of these results?

B. Local cellular pH can decrease from one-half to one pH unit depending on a variety of circumstances including ischemia, hypoxia, and inflammation due to lactic acidosis. In addition, metabolic acidosis is often one of the symptoms in complications following surgery. The investigators have proposed that HPRG acts to relieve the acidosis in these circumstances, possibly in synergy with Zn2+ ions. Propose a model that explains the mechanism of pH regulation by HPRG.

C. Other plasma proteins have been studied for their ability to bind to glycosaminoglycans. One such protein is kininogen, which is a lysine-rich protein. Like HPRG, kininogen is able to bind to glycosaminoglycans, but this binding is far less sensitive to small fluctuations in physiological pH. Why does kininogen bind to glycosaminoglycans easily? Why is the binding of kininogen less sensitive to physiological pH changes?

Explanation / Answer

a. The results can be interpreted that with the increasing cation concentration the binding capacity is also positively increasing. Under lower pH there is not much difference in the copper and zinc capacity but as the pH gets higher zinc facilitates higher binding capacity than copper.

b. A model where HPRG acts as a physiological pH sensor can explain the mechanism of pH regulation.

c.  kininogen bind to glycosaminoglycans easily due to the presence of domains D3 and D5H also zinc facilitates easy binding. Kininogen binding is less sensitive to pH changes because the pKa of the HIS side chain is much lower than that of lysine. Due to this the pKa of lysine remains positive at higher pH.

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