Structural basis for the inhibition of IAPP fibril formation by the co-chaperonin prefoldin

Ricarda Törner, Tatsiana Kupreichyk, Lothar Gremer, Elisa Colas Debled, Daphna Fenel, Sarah Schemmert, Pierre Gans, Dieter Willbold, Guy Schoehn, Wolfgang Hoyer () and Jerome Boisbouvier ()
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Ricarda Törner: University Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale (IBS)
Tatsiana Kupreichyk: Institute of Biological Information Processing (IBI-7: Structural Biochemistry) and JuStruct: Jülich Center for Structural Biology, Forschungszentrum Jülich
Lothar Gremer: Institute of Biological Information Processing (IBI-7: Structural Biochemistry) and JuStruct: Jülich Center for Structural Biology, Forschungszentrum Jülich
Elisa Colas Debled: University Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale (IBS)
Daphna Fenel: University Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale (IBS)
Sarah Schemmert: Institute of Biological Information Processing (IBI-7: Structural Biochemistry) and JuStruct: Jülich Center for Structural Biology, Forschungszentrum Jülich
Pierre Gans: University Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale (IBS)
Dieter Willbold: Institute of Biological Information Processing (IBI-7: Structural Biochemistry) and JuStruct: Jülich Center for Structural Biology, Forschungszentrum Jülich
Guy Schoehn: University Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale (IBS)
Wolfgang Hoyer: Institute of Biological Information Processing (IBI-7: Structural Biochemistry) and JuStruct: Jülich Center for Structural Biology, Forschungszentrum Jülich
Jerome Boisbouvier: University Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale (IBS)

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract Chaperones, as modulators of protein conformational states, are key cellular actors to prevent the accumulation of fibrillar aggregates. Here, we integrated kinetic investigations with structural studies to elucidate how the ubiquitous co-chaperonin prefoldin inhibits diabetes associated islet amyloid polypeptide (IAPP) fibril formation. We demonstrated that both human and archaeal prefoldin interfere similarly with the IAPP fibril elongation and secondary nucleation pathways. Using archaeal prefoldin model, we combined nuclear magnetic resonance spectroscopy with electron microscopy to establish that the inhibition of fibril formation is mediated by the binding of prefoldin’s coiled-coil helices to the flexible IAPP N-terminal segment accessible on the fibril surface and fibril ends. Atomic force microscopy demonstrates that binding of prefoldin to IAPP leads to the formation of lower amounts of aggregates, composed of shorter fibrils, clustered together. Linking structural models with observed fibrillation inhibition processes opens perspectives for understanding the interference between natural chaperones and formation of disease-associated amyloids.

Date: 2022
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DOI: 10.1038/s41467-022-30042-y

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