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Regulation of alpha-synuclein by chaperones in mammalian cells

Journal article
Authors 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
Published in Nature
Volume 577
Issue 7788
Pages 127-32
ISSN 0028-0836
Publication year 2020
Published at Department of Chemistry and Molecular Biology
Wallenberg Centre for Molecular and Translational Medicine
Pages 127-32
Language en
Links dx.doi.org/10.1038/s41586-019-1808-...
Keywords c-abl, complex, conformation, specificity, reveals, binding, forms, skp, Science & Technology - Other Topics
Subject categories Clinical Medicine

Abstract

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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