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Papers In Press, published online ahead of print October 2, 2000
Cell Biology and Anatomy, University of Arizona/College of Medicine, Tucson, AZ 85724
Corresponding Author: gregorio{at}u.arizona.edu
Strict regulation of actin thin filament length is critical for the proper functioning of the sarcomere, the basic contractile unit of myofibrils. It has been hypothesized for many years that a molecular template works together with actin filament capping proteins to efficiently regulate the length of the thin filaments. Since the barbed ends of the thin filaments are precisely aligned in the Z disk, a mechanism for regulation must exist at the pointed (free) end to ensure uniformity in their lengths. Nebulin is a giant protein (MW ~800 kDa) in skeletal muscle that has been proposed to act as a molecular ruler to specify the particular thin filament lengths characteristic of different muscles. Tropomodulin (Tmod), a pointed-end thin filament capping protein, has been shown to maintain the final length of the thin filaments. Immunofluorescence microscopy revealed that the N-terminal end of nebulin colocalizes with Tmod at the pointed ends of thin filaments. Using blot overlay, bead binding and solid-phase binding assays, it was established that 13.5 kDa of the extreme N-terminal modules of nebulin (M1-M2-M3) bind specifically to Tmod. Two Tmod isoforms, erythrocyte-Tmod (E-Tmod) which is expressed in embryonic and slow muscle fibers, and skeletal-Tmod (Sk-Tmod) which is expressed late in skeletal fast muscle differentiation, bind on overlapping sites to N-terminal recombinant nebulin fragments. Interestingly, Sk-Tmod binds to nebulin with a higher affinity (Kd~4 nM) than E-Tmod binds to nebulin (Kd~15 nM) suggesting that the Tmod-nebulin interaction exhibits isoform-specificity. These data provide evidence that Tmod and nebulin may work together as a linked mechanism to regulate thin filament lengths in skeletal muscle.
J. Biol. Chem, 10.1074/jbc.M005693200
Submitted on June 28, 2000
Accepted on October 2, 2000
The N-terminal end of nebulin interacts with tropomodulin at the pointed ends of the thin filaments
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