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Projekt Druckansicht

Analyzing filamin C homeostasis

Fachliche Zuordnung Zellbiologie
Förderung Förderung von 2010 bis 2018
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 148688621
 
Erstellungsjahr 2019

Zusammenfassung der Projektergebnisse

In the frame of the research unit we were able to establish fundamental principles of protein homeostasis (proteostasis) in muscle cells. The cochaperone BAG3 was identified as a central proteostasis factor, which balances transcription, translation and autophagy to maintain the proteome under mechanical stress. Its WW domain enables the cochaperone to contact diverse partner proteins during autophagosome formation and the regulation of transcription and translation, including the cytoskeleton protein SYNPO2/myopodin, components of the Hippo signalling cascade and regulators of the mTOR kinase. An initial trigger for the induction of BAG3-mediated proteostasis is the mechanical unfolding of the actin-crosslinking protein filamin C (FLNC) followed by cooperative binding of the diverse components of the BAG3 chaperone machinery to a mechanosensitive region of FLNC. We mapped the chaperone and cochaperone binding sites within this region and obtained evidence for a key function of the small heat shock protein HSPB8 in sensing FLNC unfolding. Finally, the biochemical characterization of the BAG3-P209L mutant variant provided insights into molecular aspects underlying BAG3-related muscle weaknesses. Biochemical experiments showed that the mutant protein retains the ability to interact with partner proteins and with its client filamin. However, it displays a conformational instability. These findings suggest that BAG3-P209L aggregation is accompanied by the sequestration of other essential proteostasis factor, which would explain the catastrophic collapse of protein homeostasis in diseased muscles.

Projektbezogene Publikationen (Auswahl)

 
 

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