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Biophys J. 2017 May 9;112(9):1742-1760. doi: 10.1016/j.bpj.2017.03.034.

Tropomodulins and Leiomodins: Actin Pointed End Caps and Nucleators in Muscles.

Author information

1
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California. Electronic address: velia@scripps.edu.
2
Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: droberto@mail.med.upenn.edu.

Abstract

Cytoskeletal structures characterized by actin filaments with uniform lengths, including the thin filaments of striated muscles and the spectrin-based membrane skeleton, use barbed and pointed-end capping proteins to control subunit addition/dissociation at filament ends. While several proteins cap the barbed end, tropomodulins (Tmods), a family of four closely related isoforms in vertebrates, are the only proteins known to specifically cap the pointed end. Tmods are ∼350 amino acids in length, and comprise alternating tropomyosin- and actin-binding sites (TMBS1, ABS1, TMBS2, and ABS2). Leiomodins (Lmods) are related in sequence to Tmods, but display important differences, including most notably the lack of TMBS2 and the presence of a C-terminal extension featuring a proline-rich domain and an actin-binding WASP-Homology 2 domain. The Lmod subfamily comprises three somewhat divergent isoforms expressed predominantly in muscle cells. Biochemically, Lmods differ from Tmods, acting as powerful nucleators of actin polymerization, not capping proteins. Structurally, Lmods and Tmods display crucial differences that correlate well with their different biochemical activities. Physiologically, loss of Lmods in striated muscle results in cardiomyopathy or nemaline myopathy, whereas complete loss of Tmods leads to failure of myofibril assembly and developmental defects. Yet, interpretation of some of the in vivo data has led to the idea that Tmods and Lmods are interchangeable or, at best, different variants of two subfamilies of pointed-end capping proteins. Here, we review and contrast the existing literature on Tmods and Lmods, and propose a model of Lmod function that attempts to reconcile the in vitro and in vivo data, whereby Lmods nucleate actin filaments that are subsequently capped by Tmods during sarcomere assembly, turnover, and repair.

PMID:
28494946
PMCID:
PMC5425412
DOI:
10.1016/j.bpj.2017.03.034
[Indexed for MEDLINE]
Free PMC Article

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