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Regulation of alpha-synuclein by chaperones in mammalian cells

Artikel i vetenskaplig tidskrift
Författare Björn Marcus Burmann
J. A. Gerez
Irena Matečko-Burmann
S. Campioni
P. Kumari
D. Ghosh
A. Mazur
Emelie E. Aspholm
Darios Šulskis
M. Wawrzyniuk
T. Bock
A. Schmidt
S. G. D. Rudiger
R. Riek
S. Hiller
Publicerad i Nature
Volym 577
Nummer/häfte 7788
Sidor 127-32
ISSN 0028-0836
Publiceringsår 2020
Publicerad vid Institutionen för kemi och molekylärbiologi
Wallenberg Centre for Molecular and Translational Medicine
Sidor 127-32
Språk en
Länkar dx.doi.org/10.1038/s41586-019-1808-...
Ämnesord c-abl, complex, conformation, specificity, reveals, binding, forms, skp, Science & Technology - Other Topics
Ämneskategorier Klinisk medicin

Sammanfattning

Neurodegeneration in patients with Parkinson's disease is correlated with the occurrence of Lewy bodies-intracellular inclusions that contain aggregates of the intrinsically disordered protein alpha-synuclein(1). The aggregation propensity of alpha-synuclein in cells is modulated by specific factors that include post-translational modifications(2,3), Abelson-kinase-mediated phosphorylation(4,5) and interactions with intracellular machineries such as molecular chaperones, although the underlying mechanisms are unclear(6-8). Here we systematically characterize the interaction of molecular chaperones with alpha-synuclein in vitro as well as in cells at the atomic level. We find that six highly divergent molecular chaperones commonly recognize a canonical motif in alpha-synuclein, consisting of the N terminus and a segment around Tyr39, and hinder the aggregation of alpha-synuclein. NMR experiments(9) in cells show that the same transient interaction pattern is preserved inside living mammalian cells. Specific inhibition of the interactions between alpha-synuclein and the chaperone HSC70 and members of the HSP90 family, including HSP90 beta, results in transient membrane binding and triggers a remarkable re-localization of alpha-synuclein to the mitochondria and concomitant formation of aggregates. Phosphorylation of alpha-synuclein at Tyr39 directly impairs the interaction of alpha-synuclein with chaperones, thus providing a functional explanation for the role of Abelson kinase in Parkinson's disease. Our results establish a master regulatory mechanism of alpha-synuclein function and aggregation in mammalian cells, extending the functional repertoire of molecular chaperones and highlighting new perspectives for therapeutic interventions for Parkinson's disease.

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