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Originally published as MBC in Press, 10.1091/mbc.E07-07-0690 on February 13, 2008

Vol. 19, Issue 5, 1837-1847, May 2008

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Nebulin Interacts with CapZ and Regulates Thin Filament Architecture within the Z-Disc

Christopher T. Pappas*, Nandini Bhattacharya{dagger}, John A. Cooper{dagger}, and Carol C. Gregorio*,{ddagger}

Departments of {ddagger}Cell Biology and Anatomy and *Molecular and Cellular Biology, The University of Arizona, Tucson, AZ 85721-0106; and {dagger}Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110

Submitted July 23, 2007; Revised January 28, 2008; Accepted February 6, 2008
Monitoring Editor: Yu-Li Wang

The barbed ends of actin filaments in striated muscle are anchored within the Z-disc and capped by CapZ; this protein blocks actin polymerization and depolymerization in vitro. The mature lengths of the thin filaments are likely specified by the giant "molecular ruler" nebulin, which spans the length of the thin filament. Here, we report that CapZ specifically interacts with the C terminus of nebulin (modules 160–164) in blot overlay, solid-phase binding, tryptophan fluorescence, and SPOTs membrane assays. Binding of nebulin modules 160–164 to CapZ does not affect the ability of CapZ to cap actin filaments in vitro, consistent with our observation that neither of the two C-terminal actin binding regions of CapZ is necessary for its interaction with nebulin. Knockdown of nebulin in chick skeletal myotubes using small interfering RNA results in a reduction of assembled CapZ, and, strikingly, a loss of the uniform alignment of the barbed ends of the actin filaments. These data suggest that nebulin restricts the position of thin filament barbed ends to the Z-disc via a direct interaction with CapZ. We propose a novel molecular model of Z-disc architecture in which nebulin interacts with CapZ from a thin filament of an adjacent sarcomere, thus providing a structural link between sarcomeres.

This was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E07-07-0690) on February 13, 2008.

Address correspondence to: Carol C. Gregorio (gregorio{at}u.arizona.edu)




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