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Mol Biol Cell. 2016 Dec 1;27(24):3869-3882. Epub 2016 Oct 12.

Nebulette is a powerful cytolinker organizing desmin and actin in mouse hearts.

Author information

1
Department of Biochemistry & Biophysics, Texas A&M University, College Station, TX 77843-3474.
2
Division of Molecular Genetics, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany.
3
Center of Basic Research, Biomedical Research Foundation Academy of Athens, Athens 11527, Greece.
4
Institute of Neuropathology, University Hospital Erlangen, D-91054 Erlangen, Germany.
5
Department of Biochemistry & Biophysics, Texas A&M University, College Station, TX 77843-3474 gconover@tamu.edu.

Abstract

In the hearts of patients bearing nebulette mutations, a severe general disorganization in cardiomyocytes of the extrasarcomeric desmin intermediate filament system is frequently observed. However, the molecular and functional relationship between the desmin cytoskeleton and nebulette-containing sarcomeres is still unclear. Here we report a high-affinity in vitro interaction between nebulette and desmin filaments. A major interaction site has been mapped to the desmin α-helical rod domain, indicating that the filament core is directly involved in the binding of nebulette. The disease-mutant desmin variants E245D and T453I exhibited increased binding affinity for nebulette, delayed filament assembly kinetics, and caused significant weakening of networks. In isolated chick cardiomyocytes and sections from canine heart, we revealed by ground-state depletion and confocal microscopies that module 5 of nebulette extends outward from Z-disk-associated desmin filaments toward the center of the sarcomere. Accordingly, in the myocardium of Des-/- mice, elevated levels of cardiac actin correlated with alterations in the distribution of nebulette. Our data suggest that a well-organized desmin network is required to accommodate an optimal conformation of nebulette on sarcomeres to bind and recruit cardiac α-actin. Hence we propose that nebulette acts in synergy with nebulin to reinforce and temporally fine-tune striated muscle relaxation-contraction cycles.

PMID:
27733623
PMCID:
PMC5170609
DOI:
10.1091/mbc.E16-04-0237
[Indexed for MEDLINE]
Free PMC Article

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