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MBC in Press, published online ahead of print February 13, 2008
Mol. Biol. Cell 10.1091/mbc.E07-07-0690

A more recent version of this article appeared on May 1, 2008
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Submitted on July 23, 2007
Revised on January 28, 2008
Accepted on February 6, 2008

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; {dagger}Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis MO

Monitoring Editor: Yu-Li Wang

The barbed ends of actin filaments in striated muscle are anchored within the Z-disk 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. Knock-down of nebulin in chick skeletal myotubes using siRNA 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-disk via a direct interaction with CapZ. We propose a novel molecular model of Z-disk architecture in which nebulin interacts with CapZ from a thin filament of an adjacent sarcomere, thus providing a structural link between sarcomeres.

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






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