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-te rm treatment is the deposition of beta2-microglobulin (beta 2m) as amyloid fibers within the joint space. However, the intrinsic propensity of isolate d beta2;m protein to initiate in vitro fiber formation is negligible under conditions matched to the neutral pH and ionic conditions of serum. Here, w e present evidence for a novel interaction between beta 2m and CU2+ at a co ncentration 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 C a2+ or Zn2+ Despite maintaining a native-like conformation upon Cu2+ bindin g, the folded protein is unusually destabilized against thermal and urea de naturation. We further demonstrate that destabilization by Cu2+ uniquely pr omotes de nova fiber formation at 37 degreesC and neutral pH. Since the inc idence of amyloidosis is dramatically reduced upon elimination of copper fr om dialysis membranes, our results provide a molecular understanding for di alysis-associated amyloid formation by beta 2m. (C) 2001 Academic Press.