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Vol. 15, Issue 5, 2335-2346, May 2004

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Desmin Aggregate Formation by R120G B-Crystallin Is Caused by Altered Filament Interactions and Is Dependent upon Network Status in Cells

Ming Der Perng ^*, Shu Fang Wen ^*, Paul van den IJssel  , Alan R. Prescott , and Roy A. Quinlan ^* 

^* School of Biological and Biomedical Sciences, The University of Durham, Durham DH1 3LE, United Kingdom.; CHIPs, School of Life Sciences, Medical Science Institute, The University, Dundee DD1 5EH, Scotland

Submitted December 16, 2003; Revised February 3, 2004; Accepted February 10, 2004
Monitoring Editor: Paul Matsudaira

The R120G mutation in B-crystallin causes desmin-related myopathy. There have been a number of mechanisms proposed to explain the disease process, from altered protein processing to loss of chaperone function. Here, we show that the mutation alters the in vitro binding characteristics of B-crystallin for desmin filaments. The apparent dissociation constant of R120G B-crystallin was decreased while the binding capacity was increased significantly and as a result, desmin filaments aggregated. These data suggest that the characteristic desmin aggregates seen as part of the disease histopathology can be caused by a direct, but altered interaction of R120G B-crystallin with desmin filaments. Transfection studies show that desmin networks in different cell backgrounds are not equally affected. Desmin networks are most vulnerable when they are being made de novo and not when they are already established. Our data also clearly demonstrate the beneficial role of wild-type B-crystallin in the formation of desmin filament networks. Collectively, our data suggest that R120G B-crystallin directly promotes desmin filament aggregation, although this gain of a function can be repressed by some cell situations. Such circumstances in muscle could explain the late onset characteristic of the myopathies caused by mutations in B-crystallin.

Abbreviations used: DRM, desmin-related myopathy; DTT, dithiothreitol IF, intermediate filament; PMSF, phenylmethylsulfonyl fluoride; sHSP, small heat shock protein.

Present address: Faculteit der Geneeskunde, Kamer B334, Free University Medical Centre, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.

Corresponding author. E-mail address: r.a.quinlan{at}durham.ac.uk.

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