title: The Z-disc proteins myotilin and FATZ-1 interact with each other and are connected to the sarcolemma via muscle-specific filamins.
abstract: 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 beta1A 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 beta1 integrins. These data shed new light on the complex organization of the Z-disc that is highly relevant to understanding muscular dystrophies.
authors.affiliation: Department of Dermatology, University Hospital, HUG, Rue Micheli-du-Crest 24, 1211 Geneva 14 Switzerland.
authors.forename: Yves
authors.initials: Y
authors.lastname: Gontier
authors.forename: Anu
authors.initials: A
authors.lastname: Taivainen
authors.forename: Lionel
authors.initials: L
authors.lastname: Fontao
authors.forename: Arnoud
authors.initials: A
authors.lastname: Sonnenberg
authors.forename: Arjan
authors.initials: A
authors.lastname: van der Flier
authors.forename: Olli
authors.initials: O
authors.lastname: Carpen
authors.forename: Georgine
authors.initials: G
authors.lastname: Faulkner
authors.forename: Luca
authors.initials: L
authors.lastname: Borradori
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000502:physiology; D016466:CHO Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D064211:Connectin; D003285:Contractile Proteins / Q000235:genetics / Q000378:metabolism*; D006224:Cricetinae; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D064448:Filamins; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D009119:Muscle Contraction / Q000502:physiology; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000648:ultrastructure; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000648:ultrastructure; D009136:Muscular Dystrophies / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D012441:Saccharomyces cerevisiae; D012508:Sarcolemma / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D064211:Connectin; D003285:Contractile Proteins; D003598:Cytoskeletal Proteins; D064448:Filamins; D019012:Integrin beta1; C577290:MYOT protein, human; C419780:MYOZ1 protein, human; C419779:MYOZ2 protein, human; D008840:Microfilament Proteins; D009124:Muscle Proteins