title: Myotilin, the limb-girdle muscular dystrophy 1A (LGMD1A) protein, cross-links actin filaments and controls sarcomere assembly.
abstract: 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.
authors.affiliation: Department of Pathology and Neuroscience Program, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Paula
authors.initials: P
authors.lastname: Salmikangas
authors.forename: Peter F M
authors.initials: PF
authors.lastname: van der Ven
authors.forename: Maciej
authors.initials: M
authors.lastname: Lalowski
authors.forename: Anu
authors.initials: A
authors.lastname: Taivainen
authors.forename: Fang
authors.initials: F
authors.lastname: Zhao
authors.forename: Heli
authors.initials: H
authors.lastname: Suila
authors.forename: Rolf
authors.initials: R
authors.lastname: Schröder
authors.forename: Pekka
authors.initials: P
authors.lastname: Lappalainen
authors.forename: Dieter O
authors.initials: DO
authors.lastname: Fürst
authors.forename: Olli
authors.initials: O
authors.lastname: Carpén
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D000185:Actinin / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols; D019556:COS Cells; D018929:Cell Culture Techniques; D064211:Connectin; D006224:Cricetinae; D003520:Cyclophosphamide; D003598:Cytoskeletal Proteins; D003599:Cytoskeleton / Q000502:physiology; D004317:Doxorubicin; D015870:Gene Expression; D006801:Humans; D008840:Microfilament Proteins; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009136:Muscular Dystrophies / Q000235:genetics*; D009210:Myofibrils / Q000378:metabolism / Q000502:physiology; D011485:Protein Binding; D011994:Recombinant Proteins / Q000378:metabolism; D012518:Sarcomeres / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014750:Vincristine
chemical_list: D000911:Antibodies, Monoclonal; D064211:Connectin; D003598:Cytoskeletal Proteins; C577290:MYOT protein, human; D008840:Microfilament Proteins; D009124:Muscle Proteins; D011994:Recombinant Proteins; D000185:Actinin; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide