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BAG3 directly interacts with mutated alphaB-crystallin to suppress its aggregation and toxicity.

ABSTRACT: A homozygous disruption or genetic mutation of the bag3 gene causes progressive myofibrillar myopathy in mouse and human skeletal and cardiac muscle disorder while mutations in the small heat shock protein ?B-crystallin gene (CRYAB) are reported to be responsible for myofibrillar myopathy. Here, we demonstrate that BAG3 directly binds to wild-type ?B-crystallin and the ?B-crystallin mutant R120G, via the intermediate domain of BAG3. Peptides that inhibit this interaction in an in vitro binding assay indicate that two conserved Ile-Pro-Val regions of BAG3 are involved in the interaction with ?B-crystallin, which is similar to results showing BAG3 binding to HspB8 and HspB6. BAG3 overexpression increased ?B-crystallin R120G solubility and inhibited its intracellular aggregation in HEK293 cells. BAG3 suppressed cell death induced by ?B-crystallin R120G overexpression in differentiating C2C12 mouse myoblast cells. Our findings indicate a novel function for BAG3 in inhibiting protein aggregation caused by the genetic mutation of CRYAB responsible for human myofibrillar myopathy.

SUBMITTER: Hishiya A

PROVIDER: S-EPMC3057972 | biostudies-other | 2011 Mar

REPOSITORIES: biostudies-other

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BAG3 directly interacts with mutated alphaB-crystallin to suppress its aggregation and toxicity.

Hishiya Akinori A Salman Mortada Najem MN Carra Serena S Kampinga Harm H HH Takayama Shinichi S

PloS one 20110315 3

A homozygous disruption or genetic mutation of the bag3 gene causes progressive myofibrillar myopathy in mouse and human skeletal and cardiac muscle disorder while mutations in the small heat shock protein αB-crystallin gene (CRYAB) are reported to be responsible for myofibrillar myopathy. Here, we demonstrate that BAG3 directly binds to wild-type αB-crystallin and the αB-crystallin mutant R120G, via the intermediate domain of BAG3. Peptides that inhibit this interaction in an in vitro binding a ...[more]

PMID: 21423662

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Project description:We previously reported that zebrafish alphaB-crystallin is not constitutively expressed in nervous or muscular tissue and has reduced chaperone-like activity compared with its human ortholog. Here we characterize the tissue expression pattern and chaperone-like activity of a second zebrafish alphaB-crystallin. Expressed sequence tag analysis of adult zebrafish lens revealed the presence of a novel alpha-crystallin transcript designated cryab2 and the resulting protein alphaB2-crystallin. The deduced protein sequence was 58.2% and 50.3% identical with human alphaB-crystallin and zebrafish alphaB1-crystallin, respectively. RT-PCR showed that alphaB2-crystallin is expressed predominantly in lens but, reminiscent of mammalian alphaB-crystallin, also has lower constitutive expression in heart, brain, skeletal muscle and liver. The chaperone-like activity of purified recombinant alphaB2 protein was assayed by measuring its ability to prevent the chemically induced aggregation of alpha-lactalbumin and lysozyme. At 25 degrees C and 30 degrees C, zebrafish alphaB2 showed greater chaperone-like activity than human alphaB-crystallin, and at 35 degrees C and 40 degrees C, the human protein provided greater protection against aggregation. 2D gel electrophoresis indicated that alphaB2-crystallin makes up approximately 0.16% of total zebrafish lens protein. Zebrafish is the first species known to express two different alphaB-crystallins. Differences in primary structure, expression and chaperone-like activity suggest that the two zebrafish alphaB-crystallins perform divergent physiological roles. After gene duplication, zebrafish alphaB2 maintained the widespread protective role also found in mammalian alphaB-crystallin, while zebrafish alphaB1 adopted a more restricted, nonchaperone role in the lens. Gene duplication may have allowed these functions to separate, providing a unique model for studying structure-function relationships and the regulation of tissue-specific expression patterns.

Dataset Information

BAG3 directly interacts with mutated alphaB-crystallin to suppress its aggregation and toxicity.

Publications

BAG3 directly interacts with mutated alphaB-crystallin to suppress its aggregation and toxicity.

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