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© The Rockefeller University Press, 0021-9525/1998//1013 $5.00
The Journal of Cell Biology, Volume 143, Number 4, , 1998 1013-1027

Regular Articles

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*, Karoly Trombitás||, Thomas Centner{ddagger}, Bernhard Kolmerer{ddagger}, Gunter Stier{ddagger}, Kathleen Kunke*, Koichi Suzuki§, Franz Obermayr, Bernhard Herrmann, Henk Granzier||, Hiroyuki Sorimachi§, and Siegfried Labeit{ddagger}

* Departments of Cell Biology and Anatomy, and Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85724; {ddagger} 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

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 {alpha}-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 {alpha}-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.

Key Words: titin • {alpha}-actinin • Z-disc • titin-cap (T-cap) • sarcomere

Abbreviations used in this paper: 3-AT, 3-amino-1, 2, 4-triazole; GFP, green fluorescent protein; GST, glutathione-S-transferase; pc, post coitum; RT-PCR, reverse transcription–polymerase chain reaction; T-cap, titin-cap.

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: gregorio{at}u.arizona.edu


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