A single disulfide bond differentiates aggregation pathways of ß2-microglobulin

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Abstract

Deposition of wild-type ß2-microglobulin (ß2m) into amyloid fibrils is a complication in patients undergoing long-term hemodialysis. The native ß-sandwich fold of ß2m has a highly conserved disulfide bond linking Cys25 and Cys80. Oxidized ß2m forms needle-like amyloid fibrils at pH 2.5 in vitro, whereas reduced ß2m, at acid pH, in which the intra-chain disulfide bond is disrupted, cannot form typical fibrils. Instead, reduced ß2m forms thinner and more flexible filaments. To uncover the difference in molecular mechanisms underlying the aggregation of the oxidized and reduced ß2m, we performed molecular dynamics simulations of ß2m oligomerization under oxidized and reduced conditions. We show that, consistent with experimental observations, the oxidized ß2m forms domain-swapped dimer, in which the two proteins exchange their N-terminal segments complementing each other. In contrast, both dimers and trimers, formed by reduced ß2m, are comprised of parallel ß-sheets between monomers and stabilized by the hydrogen bond network along the backbone. The oligomerized monomers are in extended conformations, capable of further aggregation. We find that both reduced and oxidized dimers are thermodynamically less stable than their corresponding monomers, indicating that ß2m oligomerization is not accompanied by the formation of a thermodynamically stable dimer. Our studies suggest that the different aggregation pathways of oxidized and reduced ß2m are dictated by the formation of distinct precursor oligomeric species that are modulated by Cys25-Cys80 disulfide-bonds. We propose that the propagation of domain swapping is the aggregation mechanism for the oxidized ß2m, while "parallel stacking" of partially unfolded ß2m is the aggregation mechanism for the reduced ß2m.

Original languageEnglish (US)
Pages (from-to)473-482
Number of pages10
JournalJournal of Molecular Biology
Volume354
Issue number2
DOIs
StatePublished - Nov 25 2005

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Molecular Biology

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