Mechanistic Heterogeneity in Contractile Properties of α-Tropomyosin (TPM1) Mutants Associated with Inherited Cardiomyopathies

Gupte, Tejas M.; Haque, Farah; Gangadharan, Binnu; Sunitha, Margaret S.; Mukherjee, Souhrid; Anandhan, Swetha; Rani, Deepa Selvi; Mukundan, Namita; Jambekar, Amruta; Thangaraj, Kumarasamy; Sowdhamini, Ramanathan; Sommese, Ruth F.; Nag, Suman; Spudich, James A.; Mercer, John A.

doi:10.1074/jbc.m114.596676

Cited by 46 publications

(46 citation statements)

References 68 publications

(81 reference statements)

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“…A substitution by a basic residue may allow new electrostatic interactions to form with the negatively charged F-actin surface. In agreement with our calculation, a co-sedimentation measurement of Tpm-actin binding showed a two-fold increase in affinity from the WT to L185R (Gupte et al 2015). This mutation was found to increase the overall thermal stability of Tpm (Chang et al 2014;Gupte et al 2015).…”

Section: Discussion Of Tpm Mutationssupporting

confidence: 89%

“…In agreement with our calculation, a co-sedimentation measurement of Tpm-actin binding showed a two-fold increase in affinity from the WT to L185R (Gupte et al 2015). This mutation was found to increase the overall thermal stability of Tpm (Chang et al 2014;Gupte et al 2015). Indeed, our flexibility analysis found lower RMSF in L185R than the WT (see Table 1) and altered local flexibility near ALA1, ALA5, and E218 (see Fig S8 in the Supporting Information).…”

Section: Discussion Of Tpm Mutationssupporting

confidence: 89%

“…A recent computational energy-landscape study also found the E62Q mutation weakens actin-Tpm interaction ). However, this mutation did not seem to change actin-binding affinity in a co-sedimentation study (Gupte et al 2015) although further studies are needed to confirm this finding. Since E62 is at the f position of the heptad repeat, the E62Q mutation is not expected to destabilize the Tpm coiled coil structure which is consistent with the finding of intact thermal stability (Chang et al 2014).…”

Section: Discussion Of Tpm Mutationsmentioning

confidence: 41%

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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: Discussion Of Tpm Mutationssupporting

confidence: 89%

Section: Discussion Of Tpm Mutationssupporting

confidence: 89%

Section: Discussion Of Tpm Mutationsmentioning

confidence: 41%

See 1 more Smart Citation

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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“…Kobayashi et al, 2013;Lin et al, 1996;Mirza et al, 2005;Tobacman et al, 1999). More recent studies have used human β-cardiac myosin, where some specific differences in biochemical parameters were found compared with earlier nonhuman myosin studies (Bloemink et al, 2014;Deacon et al, 2012;Gupte et al, 2015;Sommese et al, 2013b). Regardless of the source of the mammalian myosin, however, the general paradigm holds true that HCM mutations in tropomyosin or troponin are sensitizers to Ca 2+ (e.g.…”

Section: + -Desensitizing Respectivelymentioning

confidence: 96%

“…Our studies use both the two-component human system of actin and myosin (Aksel et al, 2015;Sommese et al, 2013b) and the six-component reconstituted human system: actin, myosin, Tm, TnC, TnI, and TnT (Gupte et al, 2015;Sommese et al, 2013a). From the considerations described here and elsewhere (Spudich, 2015), it is possible that many of the HCM mutations in the motor domain of myosin alter the effects of a putative MyBP-C, titin or myosin S2 interaction with the mesa surface.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Effects of hypertrophic and dilated cardiomyopathy mutations on power output by human β-cardiac myosin

Spudich

Aksel

Bartholomew

et al. 2016

Journal of Experimental Biology

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Hypertrophic cardiomyopathy is the most frequently occurring inherited cardiovascular disease, with a prevalence of more than one in 500 individuals worldwide. Genetically acquired dilated cardiomyopathy is a related disease that is less prevalent. Both are caused by mutations in the genes encoding the fundamental forcegenerating protein machinery of the cardiac muscle sarcomere, including human β-cardiac myosin, the motor protein that powers ventricular contraction. Despite numerous studies, most performed with non-human or non-cardiac myosin, there is no clear consensus about the mechanism of action of these mutations on the function of human β-cardiac myosin. We are using a recombinantly expressed human β-cardiac myosin motor domain along with conventional and new methodologies to characterize the forces and velocities of the mutant myosins compared with wild type. Our studies are extending beyond myosin interactions with pure actin filaments to include the interaction of myosin with regulated actin filaments containing tropomyosin and troponin, the roles of regulatory light chain phosphorylation on the functions of the system, and the possible roles of myosin binding protein-C and titin, important regulatory components of both cardiac and skeletal muscles.

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TPM1 polymorphisms and nonsyndromic orofacial clefts susceptibility in a Chinese Han population

Qian

et al. 2016

American J of Med Genetics Pt A

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Located at 15q22 a susceptibility region for nonsyndromic orofacial clefts (NSOC), TPM1 encodes a group of highly conserved ubiquitous actin-binding proteins involved in the muscle contraction and cytoskeleton organization. Considering the multiple functions of TPM1 gene, we investigated the potential relationship between TPM1 polymorphisms and risk of NSOC in a Chinese Han population. Four tag single nucleotide polymorphisms (tSNPs) of TPM1 (rs11071720, rs3803499, rs12148828, and rs1972041) were selected to conduct a case-control study with 673 NSOC patients and 705 unrelated healthy controls from a Chinese Han population. The SNPs were genotyped by the IPLEX Sequenom MassARRAY platform. SNP rs1972041GA showed a decreased risk of NSOC in heterozygotes (P = 0.038, OR = 0.77, 95%CI = [0.61, 0.99]). Further stratified analysis revealed an enhanced protective effect of the minor allele G at rs197204 on lip with cleft palate (CLP) and cleft lip with or without cleft palate (CL/P) groups under a codominant or dominant model. No association was observed between the remaining three markers (rs11071720, rs3803499, and rs12148828) and NSOC as well as its subgroups. TPM1 polymorphisms might contribute to the etiology of NSOC, and more emphasis should be placed on TPM1 during craniofacial development.

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Mechanistic Heterogeneity in Contractile Properties of α-Tropomyosin (TPM1) Mutants Associated with Inherited Cardiomyopathies

Cited by 46 publications

References 68 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

Effects of hypertrophic and dilated cardiomyopathy mutations on power output by human β-cardiac myosin

TPM1 polymorphisms and nonsyndromic orofacial clefts susceptibility in a Chinese Han population

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