K3 fragment of amyloidogenic β2-microglobulin forms ion channels: Implication for dialysis related amyloidosis

Mirela Mustata, Ricardo Capone, Hyunbum Jang, Fernando Teran Arce, Srinivasan Ramachandran, Ratnesh Lal, Ruth Nussinov

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

Abstract

β2-microglobulin (β2m) amyloid deposits are linked to dialysis-related amyloidosis (DRA) in hemodialysis patients. The mechanism by which β2m causes DRA is not understood. It is also unclear whether only the full-length β2m induces pathophysiology or if proteolytic fragments are sufficient for inducing this effect. Ser20-Lys41 (K3) is a digestion fragment of full-length β2m. Solid state NMR (ssNMR) combined with X-ray diffraction and atomic force microscopy (AFM) revealed the characteristic oligomeric amyloid conformation of the U-turn β-strand-turn-β-strand motif stacked in parallel and stabilized by intermolecular interactions also shown by Aβ9-40/ Aβ17-42 and the CA150 WW domain. Here we use the K3 U-turn atomic coordinates and molecular dynamic (MD) simulations to model K3 channels in the membrane. Consistent with previous AFM imaging of other amyloids that show channel-like structures in the membrane, in the simulations K3 also forms ion channels with 3-6 loosely attached mobile subunits. We carry out AFM, single channel electrical recording, and fluorescence imaging experiments. AFM images display 3D ion channel topography with shapes, morphologies, and dimensions consistent with the theoretical model. Electrical conductance measurements indicate multiple single channel conductances, suggesting that various K3 oligomer sizes can constitute the channel structure. Fluorescence measurements in kidney cells show channel-mediated cell calcium uptake. These results suggest that the β2m-induced DRA can be mediated by ion channels formed by its K3 fragment. Because the β-strand-turn-β-strand motif appears to be a universal amyloid feature, its ability to form ion channels further suggests that the motif may play a generic role in toxicity.

Original languageEnglish (US)
Pages (from-to)14938-14945
Number of pages8
JournalJournal of the American Chemical Society
Volume131
Issue number41
DOIs
StatePublished - Oct 21 2009
Externally publishedYes

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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