Unusual splicing events result in distinct Xin isoforms that associate differentially with filamin c and Mena/VASP.
Filamin c is the predominantly expressed filamin isoform in striated muscles. It is localized in myofibrillar Z-discs, where it binds FATZ and myotilin, and in myotendinous junctions and intercalated discs. Here, we identify Xin, the protein encoded by the human gene 'cardiomyopathy associated 1' (CMYA1) as filamin c binding partner at these specialized structures where the ends of myofibrils are attached to the sarcolemma. Xin directly binds the EVH1 domain proteins Mena and VASP. In the adult heart, Xin and Mena/VASP colocalize with filamin c in intercalated discs. In cultured cardiomyocytes, the proteins also localize in the nonstriated part of myofibrils, where sarcomeres are assembled and an extensive reorganization of the actin cytoskeleton occurs. Unusual intraexonic splicing events result in the existence of three Xin isoforms that associate differentially with its ligands. The identification of the complex filamin c-Xin-Mena/VASP provides a first glance on the role of Xin in the molecular mechanisms involved in developmental and adaptive remodeling of the actin cytoskeleton during cardiac morphogenesis and sarcomere assembly.
van der Ven
Peter F M
PF
Department of Molecular Cell Biology, University of Bonn, Ulrich-Haberland-Str. 61a, D-53121 Bonn, Germany. pvdven@uni-bonn.de
Ehler
Elisabeth
E
Vakeel
Padmanabhan
P
Eulitz
Stefan
S
Schenk
Jörg A
JA
Milting
Hendrik
H
Micheel
Burkhard
B
Fürst
Dieter O
DO
D017398:Alternative Splicing; D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D015815:Cell Adhesion Molecules / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D003285:Contractile Proteins / Q000032:analysis / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D005091:Exons; D064448:Filamins; D014644:Genetic Variation; D006801:Humans; D008840:Microfilament Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D010750:Phosphoproteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics; D051381:Rats; D000098662:Vasodilator-Stimulated Phosphoprotein
D015815:Cell Adhesion Molecules; D003285:Contractile Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; C102176:Enah protein, mouse; D064448:Filamins; D008840:Microfilament Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D020033:Protein Isoforms; C512114:XIRP1 protein, human; C118478:Xin protein, mouse; D000098662:Vasodilator-Stimulated Phosphoprotein