Karyopherins and condensates.

Area of Science:

• Molecular Biology
• Neuroscience
• Biophysics

Background:

• Several aggregation-prone RNA-binding proteins (RBPs) like FUS, EWS, TAF15, hnRNP A1, hnRNP A2, and TDP-43 are implicated in neurodegenerative diseases.
• The nuclear-cytoplasmic transport of these RBPs is regulated by karyopherins (Kaps), a family of nuclear transport factors.
• Kaps not only facilitate RBP transport but also possess molecular chaperone activity, inhibiting RBP self-association and aggregation.

Purpose of the Study:

• To review physical data on the mechanisms of self-association of disease-associated RBPs.
• To correlate RBP self-association mechanisms with the inhibitory effects of Kaps.
• To understand how Kaps inhibit RBP aggregation.

Main Methods:

• Review of physical data on RBP self-association (liquid-liquid phase separation, amyloid fiber formation).
• Analysis of biophysical, biochemical, and cell biological data on Kap-mediated inhibition of RBP self-association.
• Examination of the structural basis for Kap chaperone activity.

Main Results:

• Disease-associated RBPs self-associate through liquid-liquid phase separation and amyloid fiber formation.
• Kap chaperone activity is compromised in disease-causing RBP mutants.
• Kaps inhibit RBP self-association by engaging multiple regions of cargo proteins via large, physically diverse surfaces.

Conclusions:

• Kaps are crucial molecular chaperones that prevent the aggregation of disease-associated RBPs.
• Impaired Kap chaperone activity contributes to the pathogenesis of neurodegenerative diseases.
• The extensive interaction surfaces of Kaps are key to their broad chaperone efficacy against RBP self-association.