Kidney dialysis-associated amyloidosis: a molecular role for copper in fiber formation

In the US alone, more than 250,000 people have impaired renal function that necessitates treatment by dialysis. A debilitating complication of long-term treatment is the deposition of β2-microglobulin (β2m) as amyloid fibers within the joint space. However, the intrinsic propensity of isolated β2;m protein to initiate in vitro fiber formation is negligible under conditions matched to the neutral pH and ionic conditions of serum. Here, we present evidence for a novel interaction between β2m and Cu2+ at a concentration within institutionally recommended limits for this metal ion in dialysate solution. Mass spectrometry, using electrospray ionization from native conditions, demonstrates that the binding of Cu2+ is specific over Ca2+ or Zn2+. Despite maintaining a native-like conformation upon Cu2+ binding, the folded protein is unusually destabilized against thermal and urea denaturation. We further demonstrate that destabilization by Cu2+ uniquely promotes de novo fiber formation at 37°C and neutral pH. Since the incidence of amyloidosis is dramatically reduced upon elimination of copper from dialysis membranes, our results provide a molecular understanding for dialysis-associated amyloid formation by β2m.