Plasmodium chaperonin TRiC/CCT identified as a target of the antihistamine clemastine using parallel chemoproteomic strategy.

Proceedings of the National Academy of Sciences of the United States of America
Kuan-Yi LuEmily R Derbyshire

Abstract

The antihistamine clemastine inhibits multiple stages of the Plasmodium parasite that causes malaria, but the molecular targets responsible for its parasite inhibition were unknown. Here, we applied parallel chemoproteomic platforms to discover the mechanism of action of clemastine and identify that clemastine binds to the Plasmodium falciparum TCP-1 ring complex or chaperonin containing TCP-1 (TRiC/CCT), an essential heterooligomeric complex required for de novo cytoskeletal protein folding. Clemastine destabilized all eight P. falciparum TRiC subunits based on thermal proteome profiling (TPP). Further analysis using stability of proteins from rates of oxidation (SPROX) revealed a clemastine-induced thermodynamic stabilization of the Plasmodium TRiC delta subunit, suggesting an interaction with this protein subunit. We demonstrate that clemastine reduces levels of the major TRiC substrate tubulin in P. falciparum parasites. In addition, clemastine treatment leads to disorientation of Plasmodium mitotic spindles during the asexual reproduction and results in aberrant tubulin morphology suggesting protein aggregation. This clemastine-induced disruption of TRiC function is not observed in human host cells, demonstrating a species...Continue Reading

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Citations

Sep 17, 2020·Chembiochem : a European Journal of Chemical Biology·Kuan-Yi Lu
Aug 1, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Diana FontinhaMiguel Prudêncio
Dec 29, 2020·Cell Chemical Biology·Jaeyoung HaSeung Bum Park
May 18, 2021·Chembiochem : a European Journal of Chemical Biology·Kuan-Yi LuEmily R Derbyshire
Jul 1, 2020·ACS Chemical Biology·Alice L HerneisenSebastian Lourido
Dec 12, 2020·ACS Chemical Biology·Nancy WiebelhausMichael C Fitzgerald

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