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J. Biol. Chem., Vol. 278, Issue 41, 40000-40009, October 10, 2003

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Tropomodulin Contains Two Actin Filament Pointed End-capping Domains^*

Velia M. Fowler  , Norma J. Greenfield ¶ and Jeannette Moyer 

From the Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037 and the ^¶University of Medicine and Dentistry of New Jersey—Robert Wood Johnson Medical School, Piscataway, New Jersey 08854-5635

Tropomodulin 1 (Tmod1) is a 40-kDa tropomyosin binding and actin filament pointed end-capping protein that regulates pointed end dynamics and controls thin filament length in striated muscle. In vitro, the capping affinity of Tmod1 for tropomyosin-actin filaments (K_d 50 pM) is several thousand-fold greater than for capping of pure actin filaments (K_d 0.1 µM). The tropomyosin-binding region of Tmod1 has been localized to the amino-terminal portion between residues 1 and 130, but the location of the actin-capping domain is not known. We have now identified two distinct actin-capping regions on Tmod1 by testing a series of recombinant Tmod1 fragments for their ability to inhibit actin elongation from gelsolin-actin seeds using pyrene-actin polymerization assays. The carboxyl-terminal portion of Tmod1 (residues 160–359) contains the principal actin-capping activity (K_d 0.4 µM), requiring residues between 323 and 359 for full activity, whereas the amino-terminal portion of Tmod1 (residues 1–130) contains a second, weaker actin-capping activity (K_d 1.8 µM). Interestingly, 160–359 but not 1–130 enhances spontaneous actin nucleation, suggesting that the carboxyl-terminal domain may bind to two actin subunits across the actin helix at the pointed end, whereas the amino-terminal domain may bind to only one actin subunit. On the other hand, the actin-capping activity of the amino-terminal but not the carboxyl-terminal portion of Tmod1 is enhanced several thousand-fold in the presence of skeletal muscle tropomyosin. We conclude that the carboxyl-terminal capping domain of Tmod1 contains a TM-independent actin pointed end-capping activity, whereas the amino-terminal domain contains a TM-regulated pointed end actin-capping activity.

Received for publication, June 27, 2003

^* This work was supported by NIGMS, National Institutes of Health, Grant GM-34225 (to V. M. F.) and by American Heart Association Grant 0256468T (to N. J. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. This is TSRI manuscript No. 15907-CB.

To whom correspondence should be addressed: Dept. of Cell Biology, CB163, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-784-8277; Fax: 858-784-8753; E-mail: velia{at}scripps.edu.

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