Prakasam, Thirumurugan;
Hunashal, Yamanappa;
Cantarutti, Cristina;
Giorgetti, Sofia;
Faravelli, Giulia;
Mondani, Valentina;
Sharma, Sudhir Kumar;
... Esposito, Gennaro; + view all
(2021)
Topologically non-trivial metal-organic assemblies inhibit beta(2)-microglobulin amyloidogenesis.
Cell Reports Physical Science
, 2
(7)
, Article 100477. 10.1016/j.xcrp.2021.100477.
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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.
| Type: | Article |
|---|---|
| Title: | Topologically non-trivial metal-organic assemblies inhibit beta(2)-microglobulin amyloidogenesis |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.xcrp.2021.100477 |
| Publisher version: | http://dx.doi.org/10.1016/j.xcrp.2021.100477 |
| Language: | English |
| Additional information: | This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
| Keywords: | Science & Technology, Physical Sciences, Technology, Chemistry, Multidisciplinary, Energy & Fuels, Materials Science, Multidisciplinary, Physics, Multidisciplinary, Chemistry, Materials Science, Physics, ALPHA-B-CRYSTALLIN, PHARMACOLOGICAL CHAPERONES, GOLD NANOPARTICLES, COMMON MECHANISM, AMYLOID-BETA, PROTEIN, BINDING, NMR, FIBRILLOGENESIS, AGGREGATION |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10186596 |
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