Topologically non-trivial metal-organic assemblies inhibit β2-microglobulin amyloidogenesis

Thirumurugan Prakasam, Yamanappa Hunashal, Cristina Cantarutti, Sofia Giorgetti, Giulia Faravelli, Valentina Mondani, Sudhir Kumar Sharma, Ramesh Jagannathan, Giovanni Palmisano, Vittorio Bellotti, Federico Fogolari, John Carl Olsen, Ali Trabolsi, Gennaro Esposito

Research output: Contribution to journalArticlepeer-review

Abstract

Inhibiting amyloid aggregation through high-turnover dynamic interactions could be an efficient strategy that is already used by small heat-shock proteins in different biological contexts. We report the interactions of three topologically non-trivial, zinc-templated metal-organic assemblies, a [2]catenane, a trefoil knot (TK), and Borromean rings, with two β2-microglobulin (β2m) variants responsible for amyloidotic pathologies. Fast exchange and similar patterns of preferred contact surface are observed by NMR, consistent with molecular dynamics simulations. In vitro fibrillation is inhibited by each complex, whereas the zinc-free TK induces protein aggregation and does not inhibit fibrillogenesis. The metal coordination imposes structural rigidity that determines the contact area on the β2m surface depending on the complex dimensions, ensuring in vitro prevention of fibrillogenesis. Administration of TK, the best protein-contacting species, to a disease-model organism, namely a Caenorhabditis elegans mutant expressing the D76N β2m variant, confirms the bioactivity potential of the knot topology and suggests new developments.

Original languageEnglish (US)
Article number100477
JournalCell Reports Physical Science
Volume2
Issue number7
DOIs
StatePublished - Jul 21 2021

Keywords

  • amyloidogenic protein interactions
  • metal-organic knots and links
  • molecular topology
  • protein folding
  • protein NMR
  • small-molecule chaperones
  • supramolecular interactions
  • β-microglobulin

ASJC Scopus subject areas

  • Physics and Astronomy(all)
  • Materials Science(all)
  • Chemistry(all)
  • Energy(all)
  • Engineering(all)

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