Tropomyosin as a Regulator of Actin Dynamics

Khaitlina, Sofia

doi:10.1016/bs.ircmb.2015.06.002

Cited by 50 publications

(40 citation statements)

References 198 publications

(237 reference statements)

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“…The canonical core residues of Tpm are subject to irregular interruptions by destabilizing residues (Kwok and Hodges 2004), including six clusters of alanines [named ''Ala clusters'' (Brown et al 2001;Kwok and Hodges 2004;McLachlan et al 1975)], two acidic residues (D137 and E218) and other polar residues (Minakata et al 2008). Tpm regulates the cooperative binding of actin-binding proteins (e.g., myosin) with filamentous actin (F-actin) in muscle and non-muscle cells (Gunning 2008), and the assembly and dynamics of F-actin (Khaitlina 2015). There are two main Tpm isoforms (a and b, or Tpm 1.1 and Tpm 2.2 in the new nomenclature, see (Geeves et al 2015) in striated muscles, which form aa homodimers or ab heterodimers.…”

Section: Introductionmentioning

confidence: 99%

Investigating the effects of tropomyosin mutations on its flexibility and interactions with filamentous actin using molecular dynamics simulation

Zheng

Hitchcock‐DeGregori

Barua

2016

J Muscle Res Cell Motil

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Tropomyosin (Tpm) is a two-chained α-helical coiled-coil protein that binds to filamentous actin (F-actin), and regulates its interactions with myosin by occupying three average positions on F-actin (blocked, closed, and open). Mutations in the Tpm are linked to heart diseases including hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). To elucidate the molecular mechanisms of Tpm mutations (including DCM mutation E54K, HCM mutations E62Q, A63V, K70T, V95A, D175N, E180G, L185R, E192K, and a designed synthetic mutation D137L) in terms of their effects on Tpm flexibility and its interactions with F-actin, we conducted extensive molecular dynamics simulations for the wild-type and mutant Tpm in complex with F-actin (total simulation time 160 ns per mutant). The mutants exhibited distinct changes (i.e., increase or decrease) in the overall and local flexibility of the Tpm coiled-coil, with each mutation causing both local and long-range modifications of the Tpm flexibility. In addition, our binding calculations revealed weakened Tpm-F-actin interactions (except for L185R, D137L and A63V) involving five periods of Tpm, which correlate with elevated fluctuation of Tpm relative to the blocked position on F-actin that may lead to easier activation and increased Ca-sensitivity. We also simulated the αβ/βα-Tpm heterodimer in comparison with the αα-Tpm homodimer, which revealed greater flexibility and weaker actin binding in the heterodimer. Our findings are consistent with a complex mechanism underlying how different Tpm mutations perturb the Tpm function in distinct ways (e.g., by affecting specific sites of Tpm), which bear no simple links to the disease phenotypes (e.g., HCM vs. DCM).

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Section: Introductionmentioning

confidence: 99%

Investigating the effects of tropomyosin mutations on its flexibility and interactions with filamentous actin using molecular dynamics simulation

Zheng

Hitchcock‐DeGregori

Barua

2016

J Muscle Res Cell Motil

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Section: Introductionmentioning

confidence: 99%

“…Whereas a few isoforms of actin form the tracks on which myosins move, there are many classes of myosin and actin binding proteins that modify actin filament assembly and function. One actin-binding protein is tropomyosin, a nearuniversal allosteric regulator of the actin filament (Gunning, Hardeman, Lappalainen, & Mulvihill, 2015;Khaitlina, 2015;Perry, 2001;Wang & Coluccio, 2010).Tropomyosins (Tpm) are a family of two-chained a-helical coiledcoil proteins that polymerize along the length of the actin filament, thus stabilizing it and conferring co-operativity in an isoform-specific Bipasha Barua and Maria Sckolnick contributed equally to this study.…”

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confidence: 99%

Distinct sites in tropomyosin specify shared and isoform‐specific regulation of myosins II and V

et al. 2018

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Muscle contraction, cytokinesis, cellular movement, and intracellular transport depend on regulated actin-myosin interaction. Most actin filaments bind one or more isoform of tropomyosin, a coiled-coil protein that stabilizes the filaments and regulates interactions with other actin-binding proteins, including myosin. Isoform-specific allosteric regulation of muscle myosin II by actin-tropomyosin is well-established while that of processive myosins, such as myosin V, which transport organelles and macromolecules in the cell periphery, is less certain. Is the regulation by tropomyosin a universal mechanism, the consequence of the conserved periodic structures of tropomyosin, or is it the result of specialized interactions between particular isoforms of myosin and tropomyosin? Here, we show that striated muscle tropomyosin, Tpm1.1, inhibits fast skeletal muscle myosin II but not myosin Va. The non-muscle tropomyosin, Tpm3.1, in contrast, activates both myosins. To decipher the molecular basis of these opposing regulatory effects, we introduced mutations at conserved surface residues within the six periodic repeats (periods) of Tpm3.1, in positions homologous or analogous to those important for regulation of skeletal muscle myosin by Tpm1.1. We identified conserved residues in the internal periods of both tropomyosin isoforms that are important for the function of myosin Va and striated myosin II. Conserved residues in the internal and C-terminal periods that correspond to Tpm3.1-specific exons inhibit myosin Va but not myosin II function. These results suggest that tropomyosins may directly impact myosin function through both general and isoform-specific mechanisms that identify actin tracks for the recruitment and function of particular myosins.

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“…The hydrophobic core residues of Tpm are subject to irregular interruptions by destabilizing residues including alanines and other polar residues, hinting for a functional role of protein flexibility . Tpm regulates the cooperative binding of myosin with filamentous actin (F‐actin) . The binding of Tpm with F‐actin involves seven quasi‐equivalent periods (denoted P1‐P7) with different contributions to actin binding .…”

Section: Introductionmentioning

confidence: 99%

Molecular dynamics simulation of tropomyosin bound to actins/myosin in the closed and open states

Zheng

Wen

2019

Proteins

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Tropomyosin (Tpm) is a dimeric coiled‐coil protein that binds to filamentous actin, and regulates actin‐myosin interaction by moving between three positions corresponding to the blocked, closed, and open states. To elucidate how Tpm undergoes transitions between these functional states, we have built structural models and conducted extensive molecular dynamics simulations of the Tpm‐actins/myosin complex in the closed and open states (total simulation time >1.4 μs). Based on the simulation trajectories, we have analyzed the dynamics and energetics of a truncated Tpm interacting with actins/myosin under the physiological conditions. Our simulations have shown distinct dynamics of four Tpm periods (P3‐P6), featuring pronounced biased fluctuations of P4 and P5 toward the open position in the closed state, which is consistent with a conformational selection mechanism for Tpm‐regulated myosin binding. Additionally, we have identified key residues of Tpm specifically binding to actins/myosin in the closed and open state. Some of them were validated as functionally important in comparison with past functional/clinical studies, and the rest will make promising targets for future mutational experiments.

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Tropomyosin as a Regulator of Actin Dynamics

Cited by 50 publications

References 198 publications

Investigating the effects of tropomyosin mutations on its flexibility and interactions with filamentous actin using molecular dynamics simulation

Investigating the effects of tropomyosin mutations on its flexibility and interactions with filamentous actin using molecular dynamics simulation

Distinct sites in tropomyosin specify shared and isoform‐specific regulation of myosins II and V

Molecular dynamics simulation of tropomyosin bound to actins/myosin in the closed and open states

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