Desmin mutations in the terminal consensus motif prevent synemin-desmin heteropolymer filament assembly.
Disorganization of the desmin network is associated with cardiac and skeletal myopathies characterized by accumulation of desmin-containing aggregates in the cells. Multiple associations of intermediate filament proteins form a network to increase mechanical and functional stability. Synemin is a desmin-associated type VI intermediate filament protein. Neither its impact on desmin network nor how it integrates into desmin filament is yet elucidated. To gain more insight into the molecular basis of these processes, we coexpressed synemin with different desmin mutants in ex vivo models. The screening of fourteen desmin mutants showed that synemin with desmin mutants revealed two behaviors. Firstly, synemin was co-localized in desmin aggregates and its coexpression decreased the number of cells containing aggregates. Secondly, synemin was excluded from the aggregates, then synemin had no effect on desmin network organization. Among fourteen desmin mutants, there were only three mutants, p.E401K, p.R406W and p.E413K, in which synemin was not found in aggregates. This behavior was correlated to the abnormal salt-bridges of desmin-dimer as seen in silico constructs. Moreover, desmin constructs in silico and published results in literature have predicted that the salt-bridges absence in the desmin filament building prevent longitudinal annealing and/or radial compaction. These results suggest that the state of desmin-filament assembly is crucial for synemin anchorage and consequently might involve mechanical and functional stability of the cytoskeletal network.
University Paris Diderot-Paris 7/CNRS EAC4413, Unit of Functional and Adaptive Biology, Laboratory of Stress and Pathologies of the Cytoskeleton, F-75013, Paris, France. myhmos@yahoo.com
Oussama
O
Chourbagi
Francine
F
Bruston
Marianna
M
Carinci
Zhigang
Z
Xue
Patrick
P
Vicart
Denise
D
Paulin
Onnik
O
Agbulut
D020816:Amino Acid Motifs / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism*; D003893:Desmin / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007381:Intermediate Filament Proteins / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary
D003893:Desmin; D007381:Intermediate Filament Proteins; C430456:desmuslin