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  • Actin is capable of polymerizing spontaneously However

    2024-04-15

    Actin is capable of polymerizing spontaneously. However, this process is relatively slow and kinetically unfavorable in cells. Formation of BHQ dimers and trimers, which can easily disassemble due to their instability, is a rate-determining step in actin polymerization [5], [6]. The shape and the length of F-actin are regulated by actin-binding proteins, which assist actin polymerization and depolymerization [1], [2], [7], [8], [9]. Some actin-binding proteins can also sequester G-actin and prevent it from being added to the filament. Proteins from the tropomodulin family, tropomodulin (Tmod) and leiomodin (Lmod), can bind both G-actin and F-actin (see reviews [10], [11]). By binding G-actin, they can sequester actin monomers or nucleate actin polymerization. They bind at the pointed end of F-actin in a tropomyosin (Tpm)-dependent fashion. Tmod caps the pointed ends of F-actin to inhibit polymerization, whereas Lmod binds at the same end but still allows filament elongation although at lower rates than in the absence of Lmod [12], [13]. Tmod and Lmod have several isoforms that are differentially expressed in various cell types [14]. Tmod1 is expressed in, but not limited to, erythrocytes, cardiac and skeletal muscle cells [15], [16], [17]. Tmod2 is expressed only in the brain [18], [19]. Tmod3 is expressed in many cell types [14], [20] and Tmod4 is expressed in adult skeletal muscle cells [21]. Of the Tmod isoforms, Tmod3 is the best actin-sequestering isoform with weak nucleation ability, while Tmod2 is the best actin-nucleating isoform [22], [23], [24]. Of the three known Lmod isoforms, Lmod1 is expressed in smooth muscle cells, whereas Lmod2 and Lmod3 are expressed in cardiac and skeletal muscle cells [14], [25], [26]. Lmods were shown to be potent nucleators of actin polymerization [27], [28]. Both Tmod and Lmod are indispensable for cytoskeleton structure and function and vital for organisms. In mice, Tmod1 knockout leads to embryonic lethality due to cardiac defects [29], [30], [31], [32], Tmod2 knockout causes reduced sensorimotor gating, impaired learning and memory [33], and Tmod3 knockout is lethal due to anemia [34]. The knockout of Lmod2 in mice causes dilated cardiomyopathy, resulting in juvenile death [35]. Mutations in the LMOD3 gene found in human patients [28] or the knockout of Lmod3 in mice [36] were shown to cause severe nemaline myopathy. In addition, the knockout of Lmod3 or Tmod4 in frog disrupted the sarcomeric assembly [37]. These findings highlight the necessity of Tmod and Lmod isoforms in maintaining normal cellular properties in various type of tissues. Understanding the structure/function relationship for the members of the tropomodulin family is necessary to unravel their exact roles in cells. Tmod and Lmod have similar domain structures, however, there are essential differences in the number of actin- and Tpm-binding sites (Fig. 1). Tmod has two Tpm-binding sites and two actin-binding sites [38], [39], [40]. Lmod, a bigger homolog of Tmod [14], [26], has the C-terminal extension that comprises a WH2 (Wiskott-Aldrich syndrome Homology 2) domain and a proline-rich region. Lmod2, the most studied Lmod isoform, contains a single Tpm-binding site [41], [42] and three actin-binding sites [12], [13], [27]. The presence of the first actin-binding site of Lmod2 is debatable. There are contradicting data obtained with Lmod2 fragments arguing the actin-binding ability of this site [12], [43], [44]. In a recent study, Boczkowska et al. [43] stated that Lmods lost pointed-end capping elements present in Tmods. This statement was based on isothermal titration calorimetry (ITC) experiments where Tmod1's N-terminal fragment A1 was shown to interact with actin while the corresponding N-terminal fragment of Lmod2 did not. The authors made the conclusion that Lmod2 lacks the N-terminal actin-binding site. On the other hand, using nuclear magnetic resonance (NMR), we showed that Lmod2's N-terminal fragment bind actin [12]. In a recent review, Fowler and Dominguez highlighted the need for additional experiments using full-length proteins to test the actin-binding function of the N-terminal region in Lmod2 [11] and to resolve the existing contradiction.