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First published online 2 August 2005
doi: 10.1242/jcs.02484
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Research Article |
1 Department of Dermatology, University Hospital, HUG, Rue Micheli-du-Crest 24, 1211 Geneva 14 Switzerland
2 Department of Pathology and Neuroscience Program, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 8, 00014 Helsinki, Finland
3 Department of Pathology, University of Turku and Turku University Central Hospital, Kiinamyllynkatu 10, 20520 Turku, Finland
4 Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX Amsterdam, The Netherlands
5 International Center for Genetic Engineering and Biotechnology, Padriciano 99, Trieste, Italy
* Author for correspondence (Luca.Borradori{at}hcuge.ch)
Accepted 21 April 2005
Myotilin and the calsarcin family member FATZ-1 (also called calsarcin-2 or myozenin-1) are recently discovered sarcomeric proteins implicated in the assembly and stabilization of the Z-discs in skeletal muscle. The essential role of myotilin in skeletal muscle is attested by the observation that certain forms of myofibrillar myopathy and limb girdle muscular dystrophy are caused by mutations in the human myotilin gene. Here we show by transfection, biochemical and/or yeast two-hybrid assay that: (1) myotilin is able to interact with the C-terminal region of FATZ-1 and that the N- or C-terminal truncations of myotilin abrogate binding; (2) myotilin can also interact with another calsarcin member, FATZ-2 (calsarcin-1, myozenin-2); (3) myotilin and FATZ-1 bind not only to the C-terminal region of filamin-C containing the Ig repeats 19-24, but also to the other two filamins, filamin-A and filamin-B, as well as the newly identified filamin-Bvar-1variant; (4) the binding of myotilin to filamin-C involves binding sites in its N-terminal region, whereas FATZ-1 associates with filamin-C via sequences within either its N- or C-terminal region; and finally, (5) the C-terminal region of filamin-C like filamin-B and filamin-Bvar-1, shows binding activity with the ß1A integrin subunit. Our findings further dissect the molecular interactions within the Z-disc that are essential for its organization, and provide evidence for a novel connection between Z-disc proteins and the sarcolemma via filamins and ß1 integrins. These data shed new light on the complex organization of the Z-disc that is highly relevant to understanding muscular dystrophies.
Key words: Myotilin, FATZ-1, Calsarcin, Z-disc, Filamins, Integrin
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