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

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.

Cardiac leiomodin2 binds to the sides of actin filaments and regulates the ATPase activity of myosin

“…This may result in the dissociation of Lmod2 from actin filaments. Our findings on the Lmod2 dependent activity of myosin II can supplement the recently published new model of cyclic activities of Lmod in sarcomeric functions and provides an in vivo support for the interpretation of our results [59]. …”

Actin assembly mechanisms at a glance

“…To overcome these kinetic barriers, de novo actin filament polymerization is initiated by actin nucleators or nucleation complexes (Dominguez, 2016;Pollard and Cooper, 2009;Quinlan and Kerkhoff, 2008). Three major classes of actin nucleators have been identified, the Arp2/3 complex, which becomes activated, for example, by nucleationpromoting factors (NPFs) of the Wiskott-Aldrich syndrome protein (WASP)/WASP-family verprolin-homologous protein (WAVE) family; the formins, which assemble into a donut-shaped dimer, where each of the subunits can bind two actin monomers; and finally, the tandem actin-binding domain nucleators, such as Spire, Cobl and leiomodin, which promote actin filament initiation by binding of G-actin to two or more of their WH2 and other actinbinding domains (Ahuja et al, 2007;Chereau et al, 2008;Dominguez, 2016;Fowler and Dominguez, 2017;Machesky and Insall, 1998;Mullins et al, 1998;Otomo et al, 2005b;Pruyne et al, 2002;Quinlan et al, 2005;Sagot et al, 2002). In addition to nucleation, formins also accelerate elongation of the fast-growing (barbed) ends of actin filaments (Otomo et al, 2005a;Romero et al, 2004;Vavylonis et al, 2006), by both attracting profilin-bound G-actin and antagonizing the abrogation of barbed end elongation by capping protein.…”

In vivo elongation of thin filaments results in heart failure

“…Although it is known that changes in thin filament lengths are linked to development of cardiac and skeletal myopathies [1][2][3][4][5], how those changes contribute to the pathophysiological mechanism of disease progression has yet to be shown. Numerous actin-binding proteins have been shown to regulate the lengths of actin filaments from their barbed ends in non-muscle cells; however, in mammalian cardiac muscle cells, where dynamic regulation of thin filament lengths occurs from the pointed ends in the center of the sarcomere, tropomodulin and leiomodin are the only proteins reported to localize to the pointed ends, and function to maintain thin filament lengths [reviewed in [6][7][8]].…”