The cardiomyopathy and lens cataract mutation in alphaB-crystallin alters its protein structure, chaperone activity, and interaction with intermediate filaments in vitro.

MD Perng, PJ Muchowski, P van Den IJssel… - The Journal of …, 1999 - europepmc.org
MD Perng, PJ Muchowski, P van Den IJssel, GJ Wu, AM Hutcheson, JI Clark, RA Quinlan
The Journal of biological chemistry, 1999europepmc.org
Desmin-related myopathy and cataract are both caused by the R120G mutation in alphaB-
crystallin. Desmin-related myopathy is one of several diseases characterized by the
coaggregation of intermediate filaments with alphaB-crystallin, and it identifies intermediate
filaments as important physiological substrates for alphaB-crystallin. Using recombinant
human alphaB-crystallin, the effects of the disease-causing mutation R120G upon the
structure and the chaperone activities of alphaB-crystallin are reported. The secondary …
Desmin-related myopathy and cataract are both caused by the R120G mutation in alphaB-crystallin. Desmin-related myopathy is one of several diseases characterized by the coaggregation of intermediate filaments with alphaB-crystallin, and it identifies intermediate filaments as important physiological substrates for alphaB-crystallin. Using recombinant human alphaB-crystallin, the effects of the disease-causing mutation R120G upon the structure and the chaperone activities of alphaB-crystallin are reported. The secondary, tertiary, and quaternary structural features of alphaB-crystallin are all altered by the mutation as deduced by near-and far-UV circular dichroism spectroscopy, size exclusion chromatography, and chymotryptic digestion assays. The R120G alphaB-crystallin is also less stable than wild type alphaB-crystallin to heat-induced denaturation. These structural changes coincide with a significant reduction in the in vitro chaperone activity of the mutant alphaB-crystallin protein, as assessed by temperature-induced protein aggregation assays. The mutation also significantly altered the interaction of alphaB-crystallin with intermediate filaments. It abolished the ability of alphaB-crystallin to prevent those filament-filament interactions required to induce gel formation while increasing alphaB-crystallin binding to assembled intermediate filaments. These activities are closely correlated to the observed disease pathologies characterized by filament aggregation accompanied by alphaB-crystallin binding. These studies provide important insight into the mechanism of alphaB-crystallin-induced aggregation of intermediate filaments that causes disease.
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