Impact of disease mutations on the desmin filament assembly process

Baer, Harald and Muecke, Norbert and Ringler, Philippe and Müller, Shirley A. and Kreplak, Laurent and Katus, Hugo A. and Aebi, Ueli and Herrmann, Harald. (2006) Impact of disease mutations on the desmin filament assembly process. Journal of molecular biology, Vol. 360, H. 5. pp. 1031-1042.

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Official URL: http://edoc.unibas.ch/dok/A5262468

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It has been documented that mutations in the human desmin gene lead to a severe type of myofibrillar myopathy, termed more specifically desminopathy, which affects cardiac and skeletal as well as smooth muscle. We showed recently that 14 recombinant versions of these disease-causing desmin variants, all involving single amino acid substitutions in the a-helical rod domain, interfere with in vitro filament formation at distinct stages of the assembly process. We now provide mechanistic details of how these mutations affect the filament assembly process by employing anal. ultracentrifugation, time-lapse electron microscopy of neg. stained and glycerol-sprayed/low-angle rotary metal-shadowed samples, quant. scanning TEM, and viscometric studies. In particular, the sol. assembly intermediates of two of the mutated proteins exhibit unusually high s-values, compatible with octamers and other higher-order complexes. Moreover, several of the six filament-forming mutant variants deviated considerably from wild-type desmin with respect to their filament diams. and mass-per-length values. In the heteropolymeric situation with wild-type desmin, four of the mutant variants caused a pronounced "hyper-assembly", when assayed by viscometry. This indicates that the various mutations may cause abortion of filament formation by the mutant protein at distinct stages, and that some of them interfere severely with the assembly of wild-type desmin. Taken together, our findings provide novel insights into the basic intermediate filament assembly mechanisms and offer clues as to how amino acid changes within the desmin rod domain may interfere with the normal structural organization of the muscle cytoskeleton, eventually leading to desminopathy. [on SciFinder (R)]
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Former Organization Units Biozentrum > Structural Biology (Aebi)
UniBasel Contributors:Aebi, Ueli and Ringler, Philippe and Müller, Shirley
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
Last Modified:14 Sep 2012 06:50
Deposited On:22 Mar 2012 13:32

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