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Human Molecular Genetics, 2003, Vol. 12, No. 2 189-203
© 2003 Oxford University Press

Myotilin, the limb-girdle muscular dystrophy 1A (LGMD1A) protein, cross-links actin filaments and controls sarcomere assembly

Paula Salmikangas1, Peter F.M. van der Ven2, Maciej Lalowski1, Anu Taivainen1, Fang Zhao1,2, Heli Suila1, Rolf Schröder3, Pekka Lappalainen4, Dieter O. Fürst2 and Olli Carpén1,2,*

1Department of Pathology and Neuroscience Program, University of Helsinki and Helsinki University Hospital, Helsinki, Finland, 2Department of Cell Biology, University of Potsdam, Potsdam, Germany, 3Department of Neurology, University of Bonn, Bonn, Germany and 4Institute of Biotechnology, University of Helsinki, Helsinki, Finland

Received October 18, 2002; Accepted November 8, 2002

The assembly and maintenance of the muscle sarcomere requires a complex interplay of actin- and myosin-associated proteins. Myotilin is a thin filament-associated Z-disc protein that consists of two Ig-domains flanked by a unique serine-rich amino-terminus and a short carboxy-terminal tail. It binds to {alpha}-actinin and filamin c and is mutated in limb girdle muscular dystrophy 1A (LGMD1A). Here we show that myotilin also directly binds F-actin, efficiently cross-links actin filaments alone or in concert with {alpha}-actinin and prevents filament disassembly induced by Latrunculin A. Myotilin forms dimers via its carboxy-terminal half, which may be necessary for the actin-bundling activity. Overexpression of full-length myotilin but not the carboxy-terminal half induces formation of thick actin cables in non-muscle cells devoid of endogenous myotilin. The expression of myotilin in muscle cells is tightly regulated to the later stages of in vitro myofibrillogenesis, when preassembled myofibrils begin to align. Expression of either amino- or carboxy-terminally truncated myotilin fragments but not wild-type myotilin in differentiating myocytes leads to myofibril disarray. The disease association and functional characteristics indicate an indispensable role for myotilin in stabilization and anchorage of thin filaments, which may be a prerequisite for correct Z-disc organization.

* To whom correspondence should be addressed at: Department of Pathology and Neuroscience Program, University of Helsinki, Biomedicum, PO Box 63, 00014 Helsinki, Finland. Tel: +358 919125650; Fax: +358 947171964; Email: olli.carpen{at}helsinki.fi


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