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Cell Stress Chaperones. 2017 Jul;22(4):613-626. doi: 10.1007/s12192-017-0788-7. Epub 2017 May 3.

αB-crystallin is a sensor for assembly intermediates and for the subunit topology of desmin intermediate filaments.

Author information

1
Division of Molecular Genetics, German Cancer Research Center, Heidelberg, Germany.
2
Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, USA.
3
Department of Biosciences and the Biophysical Sciences Institute, University of Durham, Durham, UK.
4
Institute of Molecular Medicine, College of Life Sciences, National Tsing Hua University, Hsinchu, 300, Taiwan.
5
Institute of Neuropathology, University Hospital Erlangen, Erlangen, Germany.
6
Department of Biosciences and the Biophysical Sciences Institute, University of Durham, Durham, UK. r.a.quinlan@durham.ac.uk.

Abstract

Mutations in the small heat shock protein chaperone CRYAB (αB-crystallin/HSPB5) and the intermediate filament protein desmin, phenocopy each other causing cardiomyopathies. Whilst the binding sites for desmin on CRYAB have been determined, desmin epitopes responsible for CRYAB binding and also the parameters that determine CRYAB binding to desmin filaments are unknown. Using a combination of co-sedimentation centrifugation, viscometric assays and electron microscopy of negatively stained filaments to analyse the in vitro assembly of desmin filaments, we show that the binding of CRYAB to desmin is subject to its assembly status, to the subunit organization within filaments formed and to the integrity of the C-terminal tail domain of desmin. Our in vitro studies using a rapid assembly protocol, C-terminally truncated desmin and two disease-causing mutants (I451M and R454W) suggest that CRYAB is a sensor for the surface topology of the desmin filament. Our data also suggest that CRYAB performs an assembly chaperone role because the assembling filaments have different CRYAB-binding properties during the maturation process. We suggest that the capability of CRYAB to distinguish between filaments with different surface topologies due either to mutation (R454W) or assembly protocol is important to understanding the pathomechanism(s) of desmin-CRYAB myopathies.

KEYWORDS:

CRYAB; Cardiomyopathy; Chaperone; Desmin; Desminopathy; Intermediate filaments

PMID:
28470624
PMCID:
PMC5465037
DOI:
10.1007/s12192-017-0788-7
[Indexed for MEDLINE]
Free PMC Article

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