The sarcomeric Z-disc component myopodin is a multiadapter protein that interacts with filamin and alpha-actinin.
Here we introduce myopodin as a novel filamin C binding partner. Corroborative yeast two-hybrid and biochemical analyses indicate that the central part of myopodin that shows high homology to the closely related protein synaptopodin and that is common to all its currently known or predicted variants interacts with filamin C immunoglobulin-like domains 20-21. A detailed characterization of the previously described interaction between myopodin and alpha-actinin demonstrates for the first time that myopodin contains three independent alpha-actinin-binding sites. Newly developed myopodin-specific antibodies reveal expression at the earliest stages of in vitro differentiation of human skeletal muscle cells preceding the expression of sarcomeric alpha-actinin. Myopodin colocalizes with filamin and alpha-actinin during all stages of muscle development. By contrast, colocalization with its previously identified binding partner zyxin is restricted to early developmental stages. Genetic and cellular analyses of skeletal muscle provided direct evidence for an alternative transcriptional start site in exon three, corroborating the expression of a myopodin variant lacking the PDZ domain encoded by exons 1 and 2 in skeletal muscle. We conclude that myopodin is a multiadapter protein of the sarcomeric Z-disc that links nascent myofibrils to the sarcolemma via zyxin, and might play a role in early assembly and stabilization of the Z-disc. Mutations in FLNC, ACTN2 and several other genes encoding Z-disc-related proteins cause myopathy and cardiomyopathy. Its localization and its association with the myopathy-associated proteins filamin C and alpha-actinin make myopodin an interesting candidate for a muscle disease gene.
Linnemann
Anja
A
Institute for Cell Biology, Department of Molecular Cell Biology, University of Bonn, Bonn, Germany.
van der Ven
Peter F M
PF
Vakeel
Padmanabhan
P
Albinus
Britta
B
Simonis
Dirk
D
Bendas
Gerd
G
Schenk
Jörg A
JA
Micheel
Burkhard
B
Kley
Rudolf A
RA
Fürst
Dieter O
DO
D000185:Actinin / Q000378:metabolism*; D000328:Adult; D003285:Contractile Proteins / Q000235:genetics / Q000378:metabolism*; D064448:Filamins; D006801:Humans; D047468:Immunoprecipitation; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D012518:Sarcomeres / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
D003285:Contractile Proteins; C578661:FLNC protein, human; D064448:Filamins; D008840:Microfilament Proteins; C503979:SYNPO2 protein, human; D000185:Actinin