Tropomodulins and tropomyosins: working as a team

Abstract

Actin filaments are major components of the cytoskeleton in eukaryotic cells and are involved in vital cellular functions such as cell motility and muscle contraction. Tmod and TM are crucial constituents of the actin filament network, making their presence indispensable in living cells. Tropomyosin (TM) is an alpha-helical, coiled coil protein that covers the grooves of actin filaments and stabilizes them. Actin filament length is optimized by tropomodulin (Tmod), which caps the slow growing (pointed end) of thin filaments to inhibit polymerization or depolymerization. Tmod consists of two structurally distinct regions: the N-terminal and the C-terminal domains. The N-terminal domain contains two TM-binding sites and one TM-dependent actin-binding site, whereas the C-terminal domain contains a TM-independent actin-binding site. Tmod binds to two TM molecules and at least one actin molecule during capping. The interaction of Tmod with TM is a key regulatory factor for actin filament organization. The binding efficacy of Tmod to TM is isoform-dependent. The affinities of Tmod/TM binding influence the proper localization and capping efficiency of Tmod at the pointed end of actin filaments in cells. Here we describe how a small difference in the sequence of the TM-binding sites of Tmod may result in dramatic change in localization of Tmod in muscle cells or morphology of non-muscle cells. We also suggest most promising directions to study and elucidate the role of Tmod-TM interaction in formation and maintenance of sarcomeric and cytoskeletal structure.

Figure 1

The schematic view of Tmod1 molecule. LRR: leucine rich repeats. TM1 and TM2 are the tropomyosin-binding sites, A1 and A2 are the actin-binding sites. Amino acids sequences of the sites are presented in the insets with the helical regions indicated by grey color. Residues mutated in the sites are in capital.

Figure 2

The model of Tmod’s binding at the pointed end of the actin filament. (A) Cartoon representation of the binding of Tmod to TM and actin molecules at the pointed end. (B) and (C) Ribbon diagrams for the possible binding modes for the first and second TM-binding sites of Tmod, respectively (adapted from (Kostyukova et al. 2007)).