TY  - JOUR
AU  - Törner, Ricarda
AU  - Kupreichyk, Tatsiana
AU  - Gremer, Lothar
AU  - Debled, Elisa Colas
AU  - Fenel, Daphna
AU  - Schemmert, Sarah
AU  - Gans, Pierre
AU  - Willbold, Dieter
AU  - Schoehn, Guy
AU  - Hoyer, Wolfgang
AU  - Boisbouvier, Jerome
TI  - Structural basis for the inhibition of IAPP fibril formation by the co-chaperonin prefoldin.
JO  - Nature Communications
VL  - 13
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - FZJ-2022-02987
SP  - 2363
PY  - 2022
AB  - 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.
KW  - Amyloid: metabolism
KW  - Chaperonins
KW  - Humans
KW  - Islet Amyloid Polypeptide
KW  - Molecular Chaperones: metabolism
KW  - Amyloid (NLM Chemicals)
KW  - Islet Amyloid Polypeptide (NLM Chemicals)
KW  - Molecular Chaperones (NLM Chemicals)
KW  - prefoldin (NLM Chemicals)
KW  - Chaperonins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:35501361
C2  - pmc:PMC9061850
UR  - <Go to ISI:>//WOS:000789924700014
DO  - DOI:10.1038/s41467-022-30042-y
UR  - https://juser.fz-juelich.de/record/909069
ER  -