Indications for a novel muscular dystrophy pathway: γ-filamin, the muscle-specific filamin isoform, interacts with myotilin

PFM van der Ven, S Wiesner, P Salmikangas… - The Journal of cell …, 2000 - rupress.org
PFM van der Ven, S Wiesner, P Salmikangas, D Auerbach, M Himmel, S Kempa, K Hayeß…
The Journal of cell biology, 2000rupress.org
γ-Filamin, also called ABP-L, is a filamin isoform that is specifically expressed in striated
muscles, where it is predominantly localized in myofibrillar Z-discs. A minor fraction of the
protein shows subsarcolemmal localization. Although γ-filamin has the same overall
structure as the two other known isoforms, it is the only isoform that carries a unique
insertion in its immunoglobulin (Ig)-like domain 20. Sequencing of the genomic region
encoding this part of the molecule shows that this insert is encoded by an extra exon …
γ-Filamin, also called ABP-L, is a filamin isoform that is specifically expressed in striated muscles, where it is predominantly localized in myofibrillar Z-discs. A minor fraction of the protein shows subsarcolemmal localization. Although γ-filamin has the same overall structure as the two other known isoforms, it is the only isoform that carries a unique insertion in its immunoglobulin (Ig)-like domain 20. Sequencing of the genomic region encoding this part of the molecule shows that this insert is encoded by an extra exon. Transient transfections of the insert-bearing domain in skeletal muscle cells and cardiomyocytes show that this single domain is sufficient for targeting to developing and mature Z-discs. The yeast two-hybrid method was used to identify possible binding partners for the insert-bearing Ig-like domain 20 of γ-filamin. The two Ig-like domains of the recently described α-actinin–binding Z-disc protein myotilin were found to interact directly with this filamin domain, indicating that the amino-terminal end of γ-filamin may be indirectly anchored to α-actinin in the Z-disc via myotilin. Since defects in the myotilin gene were recently reported to cause a form of autosomal dominant limb-girdle muscular dystrophy, our findings provide a further contribution to the molecular understanding of this disease.
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