title: Indications for a novel muscular dystrophy pathway. gamma-filamin, the muscle-specific filamin isoform, interacts with myotilin.
abstract: gamma-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 gamma-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 gamma-filamin. The two Ig-like domains of the recently described alpha-actinin-binding Z-disc protein myotilin were found to interact directly with this filamin domain, indicating that the amino-terminal end of gamma-filamin may be indirectly anchored to alpha-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.
authors.affiliation: Department of Cell Biology, University of Potsdam, D-14471 Potsdam, Germany. pvdven@rz.uni-potsdam.de
authors.forename: P F
authors.initials: PF
authors.lastname: van der Ven
authors.forename: S
authors.initials: S
authors.lastname: Wiesner
authors.forename: P
authors.initials: P
authors.lastname: Salmikangas
authors.forename: D
authors.initials: D
authors.lastname: Auerbach
authors.forename: M
authors.initials: M
authors.lastname: Himmel
authors.forename: S
authors.initials: S
authors.lastname: Kempa
authors.forename: K
authors.initials: K
authors.lastname: Hayess
authors.forename: D
authors.initials: D
authors.lastname: Pacholsky
authors.forename: A
authors.initials: A
authors.lastname: Taivainen
authors.forename: R
authors.initials: R
authors.lastname: Schröder
authors.forename: O
authors.initials: O
authors.lastname: Carpén
authors.forename: D O
authors.initials: DO
authors.lastname: Fürst
mesh_terms: D000328:Adult; D000818:Animals; D002454:Cell Differentiation; D064211:Connectin; D003285:Contractile Proteins / Q000378:metabolism*; D003598:Cytoskeletal Proteins; D004251:DNA Transposable Elements; D005091:Exons; D064448:Filamins; D006801:Humans; D007136:Immunoglobulins; D008024:Ligands; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism*; D009124:Muscle Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D009136:Muscular Dystrophies / Q000209:etiology*; D009206:Myocardium / Q000737:chemistry; D009210:Myofibrils / Q000378:metabolism / Q000648:ultrastructure; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism; D021382:Protein Sorting Signals; D017434:Protein Structure, Tertiary; D013234:Stem Cells / Q000737:chemistry; D020798:Two-Hybrid System Techniques
chemical_list: D064211:Connectin; D003285:Contractile Proteins; D003598:Cytoskeletal Proteins; D004251:DNA Transposable Elements; D064448:Filamins; D007136:Immunoglobulins; D008024:Ligands; C577290:MYOT protein, human; D008840:Microfilament Proteins; D009124:Muscle Proteins; C503771:Myot protein, mouse; D020033:Protein Isoforms; D021382:Protein Sorting Signals