Titin is a giant elastic protein in vertebrate striated muscles with an unprecedented molecular mass of 3–4 megadaltons. Single molecules of titin extend from the Z-line to the M-line. Here, we define the molecular layout of titin within the Z-line; the most NH2-terminal 30 kD of titin is located at the periphery of the Z-line at the border of the adjacent sarcomere, whereas the subsequent 60 kD of titin spans the entire width of the Z-line. In vitro binding studies reveal that mammalian titins have at least four potential binding sites for α-actinin within their Z-line spanning region. Titin filaments may specify Z-line width and internal structure by varying the length of their NH2-terminal overlap and number of α-actinin binding sites that serve to cross-link the titin and thin filaments. Furthermore, we demonstrate that the NH2-terminal titin Ig repeats Z1 and Z2 in the periphery of the Z-line bind to a novel 19-kD protein, referred to as titin-cap. Using dominant-negative approaches in cardiac myocytes, both the titin Z1-Z2 domains and titin-cap are shown to be required for the structural integrity of sarcomeres, suggesting that their interaction is critical in titin filament–regulated sarcomeric assembly.
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16 November 1998
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November 16 1998
The NH2 Terminus of Titin Spans the Z-Disc: Its Interaction with a Novel 19-kD Ligand (T-cap) Is Required for Sarcomeric Integrity
Carol C. Gregorio,
Carol C. Gregorio
*Departments of Cell Biology and Anatomy, and Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85724; ‡European Molecular Biology Laboratory, 69012 Heidelberg, Germany; §Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-8657, Japan; ‖Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, Washington 99164; and ¶Max-Planck Institute for Immunobiology, D-79011 Freiburg, Germany
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Karoly Trombitás,
Karoly Trombitás
*Departments of Cell Biology and Anatomy, and Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85724; ‡European Molecular Biology Laboratory, 69012 Heidelberg, Germany; §Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-8657, Japan; ‖Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, Washington 99164; and ¶Max-Planck Institute for Immunobiology, D-79011 Freiburg, Germany
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Thomas Centner,
Thomas Centner
*Departments of Cell Biology and Anatomy, and Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85724; ‡European Molecular Biology Laboratory, 69012 Heidelberg, Germany; §Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-8657, Japan; ‖Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, Washington 99164; and ¶Max-Planck Institute for Immunobiology, D-79011 Freiburg, Germany
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Bernhard Kolmerer,
Bernhard Kolmerer
*Departments of Cell Biology and Anatomy, and Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85724; ‡European Molecular Biology Laboratory, 69012 Heidelberg, Germany; §Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-8657, Japan; ‖Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, Washington 99164; and ¶Max-Planck Institute for Immunobiology, D-79011 Freiburg, Germany
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Gunter Stier,
Gunter Stier
*Departments of Cell Biology and Anatomy, and Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85724; ‡European Molecular Biology Laboratory, 69012 Heidelberg, Germany; §Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-8657, Japan; ‖Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, Washington 99164; and ¶Max-Planck Institute for Immunobiology, D-79011 Freiburg, Germany
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Kathleen Kunke,
Kathleen Kunke
*Departments of Cell Biology and Anatomy, and Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85724; ‡European Molecular Biology Laboratory, 69012 Heidelberg, Germany; §Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-8657, Japan; ‖Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, Washington 99164; and ¶Max-Planck Institute for Immunobiology, D-79011 Freiburg, Germany
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Koichi Suzuki,
Koichi Suzuki
*Departments of Cell Biology and Anatomy, and Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85724; ‡European Molecular Biology Laboratory, 69012 Heidelberg, Germany; §Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-8657, Japan; ‖Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, Washington 99164; and ¶Max-Planck Institute for Immunobiology, D-79011 Freiburg, Germany
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Franz Obermayr,
Franz Obermayr
*Departments of Cell Biology and Anatomy, and Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85724; ‡European Molecular Biology Laboratory, 69012 Heidelberg, Germany; §Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-8657, Japan; ‖Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, Washington 99164; and ¶Max-Planck Institute for Immunobiology, D-79011 Freiburg, Germany
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Bernhard Herrmann,
Bernhard Herrmann
*Departments of Cell Biology and Anatomy, and Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85724; ‡European Molecular Biology Laboratory, 69012 Heidelberg, Germany; §Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-8657, Japan; ‖Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, Washington 99164; and ¶Max-Planck Institute for Immunobiology, D-79011 Freiburg, Germany
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Henk Granzier,
Henk Granzier
*Departments of Cell Biology and Anatomy, and Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85724; ‡European Molecular Biology Laboratory, 69012 Heidelberg, Germany; §Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-8657, Japan; ‖Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, Washington 99164; and ¶Max-Planck Institute for Immunobiology, D-79011 Freiburg, Germany
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Hiroyuki Sorimachi,
Hiroyuki Sorimachi
*Departments of Cell Biology and Anatomy, and Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85724; ‡European Molecular Biology Laboratory, 69012 Heidelberg, Germany; §Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-8657, Japan; ‖Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, Washington 99164; and ¶Max-Planck Institute for Immunobiology, D-79011 Freiburg, Germany
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Siegfried Labeit
Siegfried Labeit
*Departments of Cell Biology and Anatomy, and Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85724; ‡European Molecular Biology Laboratory, 69012 Heidelberg, Germany; §Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-8657, Japan; ‖Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, Washington 99164; and ¶Max-Planck Institute for Immunobiology, D-79011 Freiburg, Germany
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Carol C. Gregorio
*Departments of Cell Biology and Anatomy, and Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85724; ‡European Molecular Biology Laboratory, 69012 Heidelberg, Germany; §Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-8657, Japan; ‖Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, Washington 99164; and ¶Max-Planck Institute for Immunobiology, D-79011 Freiburg, Germany
Karoly Trombitás
*Departments of Cell Biology and Anatomy, and Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85724; ‡European Molecular Biology Laboratory, 69012 Heidelberg, Germany; §Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-8657, Japan; ‖Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, Washington 99164; and ¶Max-Planck Institute for Immunobiology, D-79011 Freiburg, Germany
Thomas Centner
*Departments of Cell Biology and Anatomy, and Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85724; ‡European Molecular Biology Laboratory, 69012 Heidelberg, Germany; §Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-8657, Japan; ‖Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, Washington 99164; and ¶Max-Planck Institute for Immunobiology, D-79011 Freiburg, Germany
Bernhard Kolmerer
*Departments of Cell Biology and Anatomy, and Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85724; ‡European Molecular Biology Laboratory, 69012 Heidelberg, Germany; §Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-8657, Japan; ‖Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, Washington 99164; and ¶Max-Planck Institute for Immunobiology, D-79011 Freiburg, Germany
Gunter Stier
*Departments of Cell Biology and Anatomy, and Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85724; ‡European Molecular Biology Laboratory, 69012 Heidelberg, Germany; §Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-8657, Japan; ‖Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, Washington 99164; and ¶Max-Planck Institute for Immunobiology, D-79011 Freiburg, Germany
Kathleen Kunke
*Departments of Cell Biology and Anatomy, and Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85724; ‡European Molecular Biology Laboratory, 69012 Heidelberg, Germany; §Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-8657, Japan; ‖Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, Washington 99164; and ¶Max-Planck Institute for Immunobiology, D-79011 Freiburg, Germany
Koichi Suzuki
*Departments of Cell Biology and Anatomy, and Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85724; ‡European Molecular Biology Laboratory, 69012 Heidelberg, Germany; §Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-8657, Japan; ‖Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, Washington 99164; and ¶Max-Planck Institute for Immunobiology, D-79011 Freiburg, Germany
Franz Obermayr
*Departments of Cell Biology and Anatomy, and Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85724; ‡European Molecular Biology Laboratory, 69012 Heidelberg, Germany; §Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-8657, Japan; ‖Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, Washington 99164; and ¶Max-Planck Institute for Immunobiology, D-79011 Freiburg, Germany
Bernhard Herrmann
*Departments of Cell Biology and Anatomy, and Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85724; ‡European Molecular Biology Laboratory, 69012 Heidelberg, Germany; §Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-8657, Japan; ‖Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, Washington 99164; and ¶Max-Planck Institute for Immunobiology, D-79011 Freiburg, Germany
Henk Granzier
*Departments of Cell Biology and Anatomy, and Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85724; ‡European Molecular Biology Laboratory, 69012 Heidelberg, Germany; §Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-8657, Japan; ‖Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, Washington 99164; and ¶Max-Planck Institute for Immunobiology, D-79011 Freiburg, Germany
Hiroyuki Sorimachi
*Departments of Cell Biology and Anatomy, and Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85724; ‡European Molecular Biology Laboratory, 69012 Heidelberg, Germany; §Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-8657, Japan; ‖Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, Washington 99164; and ¶Max-Planck Institute for Immunobiology, D-79011 Freiburg, Germany
Siegfried Labeit
*Departments of Cell Biology and Anatomy, and Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85724; ‡European Molecular Biology Laboratory, 69012 Heidelberg, Germany; §Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-8657, Japan; ‖Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, Washington 99164; and ¶Max-Planck Institute for Immunobiology, D-79011 Freiburg, Germany
Address all correspondence to Carol C. Gregorio, Ph.D., Department of Cell Biology and Anatomy, LSN441, University of Arizona, 1501 N. Campbell Avenue, Tucson, AZ 85724. Tel.: (520) 626-8113. Fax: (520) 626-2097. E-mail: [email protected]
Received:
March 05 1998
Revision Received:
September 30 1998
Online ISSN: 1540-8140
Print ISSN: 0021-9525
1998
J Cell Biol (1998) 143 (4): 1013–1027.
Article history
Received:
March 05 1998
Revision Received:
September 30 1998
Citation
Carol C. Gregorio, Karoly Trombitás, Thomas Centner, Bernhard Kolmerer, Gunter Stier, Kathleen Kunke, Koichi Suzuki, Franz Obermayr, Bernhard Herrmann, Henk Granzier, Hiroyuki Sorimachi, Siegfried Labeit; The NH2 Terminus of Titin Spans the Z-Disc: Its Interaction with a Novel 19-kD Ligand (T-cap) Is Required for Sarcomeric Integrity . J Cell Biol 16 November 1998; 143 (4): 1013–1027. doi: https://doi.org/10.1083/jcb.143.4.1013
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