Skip to main content
SpringerLink
Log in

Tropomyosin dynamics

  • Review
  • Published:
Journal of Muscle Research and Cell Motility Aims and scope Submit manuscript

Abstract

Tropomyosin is a two chained α-helical coiled coil protein that binds actin filaments and interacts with various actin binding proteins. Tropomyosin function depends on its ability to move to distinct locations on the surface of actin in response to the binding of different thin filament effectors. Tropomyosin dynamics plays an important role in these fluctuating interactions with actin and is thought to be fundamental to many of its biological activities. For example tropomyosin concerted movement on the surface of actin triggered by Ca2+ binding to troponin or myosin head binding to actin has been argued to be key to the cooperative allosteric regulation of muscle contraction. These large-scale motions are affected by tropomyosin internal dynamics and mechanical properties. Tropomyosin internal dynamics corresponding to smaller and more localised structural fluctuations are increasingly recognised to play an important role in its function. A thorough understanding of the coupling between local and global structural fluctuations in tropomyosin is required to understand how time dependent structural fluctuations in tropomyosin contribute to the overall thin filament dynamics and dictate their various biological activities.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

EPR:

Electron paramagnetic resonance

NMR:

Nuclear magnetic resonance

Å:

Angstrom

HCM:

Hypertrophic cardiomyopathy

DCM:

Dilated cardiomyopathy

References

  • Alahyan M, Webb MR, Marston SB, El-Mezgueldi M (2006) The mechanism of smooth muscle caldesmon–tropomyosin inhibition of the elementary steps of the actomyosin ATPase. J Biol Chem 281:19433–19448

    Article  CAS  PubMed  Google Scholar 

  • Bacchiocchi C, Lehrer SS (2002) Ca(2+)-induced movement of tropomyosin in skeletal muscle thin filaments observed by multi-site FRET. Biophys J 82:1524–1536

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bacchiocchi C, Graceffa P, Lehrer SS (2004) Myosin-induced movement of alphaalpha, alphabeta, and betabeta smooth muscle tropomyosin on actin observed by multisite FRET. Biophys J 86:2295–2307

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Barua B, Pamula MC, Hitchcock-DeGregori SE (2011) Evolutionarily conserved surface residues constitute actin binding sites of tropomyosin. Proc Natl Acad Sci USA 108:10150–10155

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Barua B, Fagnant PM, Winkelmann DA, Trybus KM, Hitchcock-DeGregori SE (2013) A periodic pattern of evolutionarily conserved basic and acidic residues constitutes the binding interface of actin–tropomyosin. J Biol Chem 288(14):9602–9609

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Behrmann E, Muller M, Penczek PA, Mannherz HG, Manstein DJ, Raunser S (2012) Structure of the rigor actin–tropomyosin-myosin complex. Cell 150:327–338

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bivin DB, Stone DB, Schneider DK, Mendelson RA (1991) Cross-helix separation of tropomyosin molecules in acto-tropomyosin as determined by neutron scattering. Biophys J 59:880–888

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Brown JH, Kim KH, Jun G, Greenfield NJ, Dominguez R, Volkmann N, Hitchcock-DeGregori SE, Cohen C (2001) Deciphering the design of the tropomyosin molecule. Proc Natl Acad Sci USA 98:8496–8501

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Brown JH, Zhou Z, Reshetnikova L, Robinson H, Yammani RD, Tobacman LS, Cohen C (2005) Structure of the mid-region of tropomyosin: bending and binding sites for actin. Proc Natl Acad Sci USA 102:18878–18883

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chandy IK, Lo JC, Ludescher RD (1999) Differential mobility of skeletal and cardiac tropomyosin on the surface of F-actin. Biochemistry 38:9286–9294

    Article  CAS  PubMed  Google Scholar 

  • Correa F, Salinas RK, Bonvin AM, Farah CS (2008) Deciphering the role of the electrostatic interactions in the alpha-tropomyosin head-to-tail complex. Proteins 73:902–917

    Article  CAS  PubMed  Google Scholar 

  • Daniel RM, Dunn RV, Finney JL, Smith JC (2003) The role of dynamics in enzyme activity. Annu Rev Biophys Biomol Struct 32:69–92

    Article  CAS  PubMed  Google Scholar 

  • Earley JJ (1991) Simple harmonic motion of tropomyosin: proposed mechanism for length-dependent regulation of muscle active tension. Am J Physiol 261:C1184–C1195

    CAS  PubMed  Google Scholar 

  • Frauenfelder H, Sligar SG, Wolynes PG (1991) The energy landscapes and motions of proteins. Science 254:1598–1603

    Article  CAS  PubMed  Google Scholar 

  • Geeves MA, Lehrer SS (1994) Dynamics of the muscle thin filament regulatory switch: the size of the cooperative unit. Biophys J 67:273–282

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Graceffa P, Lehrer SS (1980) The excimer fluorescence of pyrene-labelled tropomyosin. A probe of conformational dynamics. J Biol Chem 255:11296–11300

    CAS  PubMed  Google Scholar 

  • Greenfield NJ, Huang YJ, Palm T, Swapna GV, Monleon D, Montelione GT, Hitchcock-DeGregori SE (2001) Solution NMR structure and folding dynamics of the N terminus of a rat non-muscle alpha-tropomyosin in an engineered chimeric protein. J Mol Biol 312:833–847

    Article  CAS  PubMed  Google Scholar 

  • Greenfield NJ, Palm T, Hitchcock-DeGregori SE (2002) Structure and interactions of the carboxyl terminus of striated muscle alpha-tropomyosin: it is important to be flexible. Biophys J 83:2754–2766

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Greenfield NJ, Swapna GV, Huang Y, Palm T, Graboski S, Montelione GT, Hitchcock-DeGregori SE (2003) The structure of the carboxyl terminus of striated alpha-tropomyosin in solution reveals an unusual parallel arrangement of interacting alpha-helices. Biochemistry 42:614–619

    Article  CAS  PubMed  Google Scholar 

  • Greenfield NJ, Huang YJ, Swapna GV, Bhattacharya A, Rapp B, Singh A, Montelione GT, Hitchcock-DeGregori SE (2006) Solution NMR structure of the junction between tropomyosin molecules: implications for actin binding and regulation. J Mol Biol 364:80–96

    Article  CAS  PubMed  Google Scholar 

  • Gunning P, O’Neill G, Hardeman E (2008) Tropomyosin-based regulation of the actin cytoskeleton in time and space. Physiol Rev 88:1–35

    Article  CAS  PubMed  Google Scholar 

  • Heald RW, Hitchcock DeGregori SE (1988) The structure of the amino terminus of tropomyosin is critical for binding to actin in the absence and presence of troponin. J Biol Chem 263:5254–5259

    CAS  PubMed  Google Scholar 

  • Heller MJ, Nili M, Homsher E, Tobacman LS (2003) Cardiomyopathic tropomyosin mutations that increase thin filament Ca2+ sensitivity and tropomyosin N-domain flexibility. J Biol Chem 278:41742–41748

    Article  CAS  PubMed  Google Scholar 

  • Hitchcock DeGregori SE (1994) Structural requirements of tropomyosin for binding to filamentous actin. Adv Exp Med Biol 358:85–96

    Article  CAS  PubMed  Google Scholar 

  • Hitchcock DeGregori SE, An Y (1996) Integral repeats and a continuous coiled coil are required for binding of striated muscle tropomyosin to the regulated actin filament. J Biol Chem 271:3600–3603

    Article  CAS  PubMed  Google Scholar 

  • Hitchcock-DeGregori SE (2008) Tropomyosin: function follows structure. Adv Exp Med Biol 644:60–72

    Article  CAS  PubMed  Google Scholar 

  • Hodges RS, Mills J, McReynolds S, Kirwan JP, Tripet B, Osguthorpe D (2009) Identification of a unique “stability control region” that controls protein stability of tropomyosin: a two-stranded alpha-helical coiled-coil. J Mol Biol 392:747–762

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Holmes KC, Lehman W (2008) Gestalt-binding of tropomyosin to actin filaments. J Muscle Res Cell Motil 29:213–219

    Article  CAS  PubMed  Google Scholar 

  • Holthauzen LM, Correa F, Farah CS (2004) Ca2+-induced rolling of tropomyosin in muscle thin filaments: the alpha- and beta-band hypothesis revisited. J Biol Chem 279:15204–15213

    Article  CAS  PubMed  Google Scholar 

  • Howard J (2001) Mechanics of motor proteins and the cytoskeleton. Sinauer Associates, Sunderland 367 pp

    Google Scholar 

  • Ischii Y, Lehrer SS (1991) Two-site attachment of troponin to pyrene-labelled tropomyosin. J Biol Chem 266:6894–6903

    Google Scholar 

  • Ishii Y, Hitchcock DeGregori S, Mabuchi K, Lehrer SS (1992) Unfolding domains of recombinant fusion alpha alpha-tropomyosin. Protein Sci 1:1319–1325

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Jancso A, Graceffa P (1991) Smooth muscle tropomyosin coiled-coil dimers. Subunit composition, assembly, and end-to-end interaction. J Biol Chem 266:5891–5897

    CAS  PubMed  Google Scholar 

  • Lakkaraju SK, Hwang W (2009) Modulation of elasticity in functionally distinct domains of the tropomyosin coiled-coil. Cell Mol Bioeng 2:57–65

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lehman W, Craig R (2008) Tropomyosin and the steric mechanism of muscle regulation. Adv Exp Med Biol 644:95–109

    Article  CAS  PubMed  Google Scholar 

  • Lehman W, Craig R, Vibert P (1994) Ca2+-induced tropomyosin movement in Limulus thin filaments revealed by three dimensional reconstruction. Nature 368:65–67

    Article  CAS  PubMed  Google Scholar 

  • Lehman W, Vibert P, Uman P, Craig R (1995) Steric blocking by tropomyosin visualised in relaxed vertebrate muscle thin filaments. J Mol Biol 251:191–196

    Article  CAS  PubMed  Google Scholar 

  • Lehman W, Hatch V, Korman V, Rosol M, Thomas L, Maytum R, Geeves MA, Van Eyk JE, Tobacman LS, Craig R (2000) Tropomyosin and actin isoforms modulate the localization of tropomyosin strands on actin filaments. J Mol Biol 302:593–606

    Article  CAS  PubMed  Google Scholar 

  • Lehman W, Orzechowski M, Li XE, Fischer S, Raunser S (2013) Gestalt-binding of tropomyosin on actin during thin filament activation. J Muscle Res Cell Motil 34(3–4):1

    Google Scholar 

  • Lehrer SS, Qian Y (1990) Unfolding/refolding studies of smooth muscle tropomyosin. Evidence for a chain exchange mechanism in the preferential assembly of the native heterodimer. J Biol Chem 265:1134–1138

    CAS  PubMed  Google Scholar 

  • Lehrer SS, Betteridge DR, Graceffa P, Wong S, Seidel JC (1984) Comparison of the fluorescence and conformational properties of smooth and striated tropomyosin. Biochemistry 23:1591–1595

    Article  CAS  PubMed  Google Scholar 

  • Lehrer SS, Golitsina NL, Geeves MA (1997) Actin-tropomyosin activation of myosin subfragment 1 ATPase and thin filament cooperativity. The role of tropomyosin flexibility and end-to-end interactions. Biochemistry 36:13449–13454

    Article  CAS  PubMed  Google Scholar 

  • Li XE, Holmes KC, Lehman W, Jung H, Fischer S (2009) The shape and flexibility of tropomyosin coiled coils: implications for actin filament assembly and regulation. J Mol Biol 395(2):327–339

    Article  PubMed  Google Scholar 

  • Li XE, Lehman W, Fischer S, Holmes KC (2010) Curvature variation along the tropomyosin molecule. J Struct Biol 170:307–312

    Article  CAS  PubMed  Google Scholar 

  • Li XE, Tobacman LS, Mun JY, Craig R, Fischer S, Lehman W (2011) Tropomyosin position on F-actin revealed by EM reconstruction and computational chemistry. Biophys J 100:1005–1013

    Article  CAS  PubMed  Google Scholar 

  • Li XE, Suphamungmee W, Janco M, Geeves MA, Marston SB, Fischer S, Lehman W (2012) The flexibility of two tropomyosin mutants, D175 N and E180G, that cause hypertrophic cardiomyopathy. Biochem Biophys Res Commun 424:493–496

    Article  CAS  PubMed  Google Scholar 

  • Loong CK, Badr MA, Chase BP (2012) Tropomyosin flexural rigidity and single Ca2+ regulatory unit dynamics: implications for cooperative regulation of cardiac muscle contraction and cardiomyocyte hypertrophy. Front Physio 3(80):1–10

    Google Scholar 

  • Ly S, Lehrer SS (2012) Long-range effects of familial hypertrophic cardiomyopathy mutations E180G and D175 N on the properties of tropomyosin. Biochemistry 51:6413–6420

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Maytum R, Lehrer SS, Geeves MA (1999) Cooperativity and switching within the three-state model of muscle regulation. Biochemistry 38:1102–1110

    Article  CAS  PubMed  Google Scholar 

  • Maytum R, Konrad M, Lehrer SS, Geeves MA (2001) Regulatory properties of tropomyosin effects of length, isoform, and N- terminal sequence. Biochemistry 40:7334–7341

    Article  CAS  PubMed  Google Scholar 

  • Maytum R, Westerdorf B, Jaquet K, Geeves MA (2003) Differential regulation of the actomyosin interaction by skeletal and cardiac troponin isoforms. J Biol Chem 278:6696–6701

    Article  CAS  PubMed  Google Scholar 

  • McKillop DF, Geeves MA (1993) Regulation of the interaction between actin and myosin subfragment 1: evidence for three states of the thin filament. Biophys J 65:693–701

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Mijailovich SM, Kayser-Herold O, Li X, Griffiths H, Geeves MA (2012) Cooperative regulation of myosin-S1 binding to actin filaments by a continuous flexible Tm–Tn chain. Eur Biophys J 41:1015–1032

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Miki M, Makimura S, Saitoh T, Bunya M, Sugahara Y, Ueno Y, Kimura-Sakiyama C, Tobita H (2011) A three-dimensional FRET analysis to construct an atomic model of the actin–tropomyosin complex on a reconstituted thin filament. J Mol Biol 414:765–782

    Article  CAS  PubMed  Google Scholar 

  • Miki M, Makimura S, Sugahara Y, Yamada R, Bunya M, Saitoh T, Tobita H (2012) A three-dimensional FRET analysis to construct an atomic model of the actin–tropomyosin–troponin core domain complex on a muscle thin filament. J Mol Biol 420:40–55

    Article  CAS  PubMed  Google Scholar 

  • Minakata S, Maeda K, Oda N, Wakabayashi K, Nitanai Y, Maeda Y (2008) Two-crystal structures of tropomyosin C-terminal fragment 176-273: exposure of the hydrophobic core to the solvent destabilizes the tropomyosin molecule. Biophys J 95:710–719

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Mirza M, Robinson P, Kremneva E, Copeland O, Nikolaeva O, Watkins H, Levitsky D, Redwood C, El-Mezgueldi M, Marston S (2007) The effect of mutations in alpha tropomyosin (E40 K and E54 K), that cause familial dilated cardiomyopathy, on the regulatory mechanism of cardiac muscle thin filaments. J Biol Chem 282:13487–13497

    Article  CAS  PubMed  Google Scholar 

  • Moore JR, Li X, Nirody J, Fischer S, Lehman W (2011) Structural implications of conserved aspartate residues located in tropomyosin’s coiled-coil core. Bioarchitecture 1:250–255

    Article  PubMed Central  PubMed  Google Scholar 

  • Murakami K, Stewart M, Nozawa K, Tomii K, Kudou N, Igarashi N, ShirakiharaY, Wakatsuki S, Yasunaga T, Wakabayashi T (2008) Structural basis for tropomyosin overlap in thin (actin) filaments and the generation of a molecular swivel by troponin-T. Proc Natl Acad Sci USA 105:7200–7205

  • Narita A, Yasinaga T, Ishikawa T, Mayanagi K, Wakabayashi T (2001) Ca2+-induced switching of troponin and tropomyosin on actin filaments as revealed by electron cryomicroscopy. J Mol Biol 308:241–261

    Article  CAS  PubMed  Google Scholar 

  • Nevzorov IA, Nikolaeva OP, Kainov YA, Redwood CS, Levitsky DI (2011) Conserved noncanonical residue Gly-126 confers instability to the middle part of the tropomyosin molecule. J Biol Chem 286:15766–15772

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Nirody J, Li X, Sousa D, Sumida J, Fischer S, Lehrer SS, Lehman W (2010) Electron microscopy and molecular dynamics on a D137L mutant of tropomyosin. Biophys J 98:414a

    Article  Google Scholar 

  • Parry DAD, Squire JM (1973) Structural role of tropomyosin in muscle regulation: analysis of the X-ray patterns from relaxed and contracting muscles. J Mol Biol 75:33–55

    Article  CAS  PubMed  Google Scholar 

  • Pirani A, Xu C, Hatch V, Craig R, Tobacman LS, Lehman W (2005) Single particle analysis of relaxed and activated muscle thin filaments. J Mol Biol 346:761–772

    Article  CAS  PubMed  Google Scholar 

  • Poole KJ, Lorenz M, Evans G, Rosenbaum G, Pirani A, Craig R, Tobacman LS, Lehman W, Holmes KC (2006) A comparison of muscle thin filament models obtained from electron microscopy reconstructions and low-angle X-ray fibre diagrams from non-overlap muscle. J Struct Biol 155:273–284

    Article  CAS  PubMed  Google Scholar 

  • Rao JN, Rivera-Santiago R, Li XE, Lehman W, Dominguez R (2012) Structural analysis of smooth muscle tropomyosin alpha and beta isoforms. J Biol Chem 287:3165–3174

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Rayes RF, Kalai T, Hideg K, Geeves MA, Fajer PG (2011) Dynamics of tropomyosin in muscle fibers as monitored by saturation transfer EPR of bi-functional probe. PLoS ONE 6:e21277

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sanders C, Sykes BD, Smillie LB (1988) Comparison of the structure and dynamics of chicken gizzard and rabbit cardiac tropomyosins: 1H NMR spectroscopy and measurement of amide hydrogen exchange rates. Biochemistry 27:7000–7008

    Article  CAS  PubMed  Google Scholar 

  • Singh A, Hitchcock-DeGregori SE (2003) Local destabilization of the tropomyosin coiled coil gives the molecular flexibility required for actin binding. Biochemistry 42:14114–14121

    Article  CAS  PubMed  Google Scholar 

  • Singh A, Hitchcock-DeGregori SE (2006) Dual requirement for flexibility and specificity for binding of the coiled-coil tropomyosin to its target, actin. Structure 14:43–50

    Article  CAS  PubMed  Google Scholar 

  • Smith DA, Geeves MA (2003) Cooperative regulation of myosin-actin interactions by a continuous flexible chain II: actin–tropomyosin-troponin and regulation by calcium. Biophys J 84:3168–3180

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Smith DA, Maytum R, Geeves MA (2003) Cooperative regulation of myosin–actin interactions by a continuous flexible chain I: actin–tropomyosin systems. Biophys J 84:3155–3167

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sousa D, Cammarato A, Jang K, Graceffa P, Tobacman LS, Li XE, Lehman W (2010) Electron microscopy and persistence length analysis of semi-rigid smooth muscle tropomyosin strands. Biophys J 99:862–868

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sumida JP, Wu E, Lehrer SS (2008) Conserved asp-137 imparts flexibility to tropomyosin and affects function. J Biol Chem 283:6728–6734

    Article  CAS  PubMed  Google Scholar 

  • Szczesna D, Fajer PG (1995) The tropomyosin domain is flexible and disordered in reconstituted thin filaments. Biochemistry 34:3614–3620

    Article  CAS  PubMed  Google Scholar 

  • Tardiff JC (2010) Tropomyosin and dilated cardiomyopathy: revenge of the actinomyosin “gatekeeper”. J Am Coll Cardiol 55:330–332

    Article  CAS  PubMed  Google Scholar 

  • Tripet B, Wagschal K, Lavigne P, Mant CT, Hodges RS (2000) Effects of side-chain characteristics on stability and oligomerization state of a de novo-designed model coiled-coil: 20 amino acid substitutions in position “d”. J Mol Biol 300:377–402

    Article  CAS  PubMed  Google Scholar 

  • Vibert PJ, Haselgrove JC, Lowy J, Poulsen FR (1972) Structural changes in actin-containing filaments of muscle. J Mol Biol 71:757–767

    Article  CAS  PubMed  Google Scholar 

  • Vilfan A (2001) The binding dynamics of tropomyosin on actin. Biophys J 81:3146–3155

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wahl P, Tawada K, Auchet JC (1978) Study of tropomyosin labelled with a fluorescent probe by pulse fluorimetry in polarized light. Interaction of that protein with troponin and actin. Eur J Biochem 88:421–424

    Article  CAS  PubMed  Google Scholar 

  • Wang CL, Coluccio LM (2010) New insights into the regulation of the actin cytoskeleton by tropomyosin. Int Rev Cell Mol Biol 281:91–128

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wang H, Mao S, Chalovich JM, Marriott G (2008) Tropomyosin dynamics in cardiac thin filaments: a multisite forster resonance energy transfer and anisotropy study. Biophys J 94:4358–4369

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wegner A (1979) Equilibrium of the actin–tropomyosin interaction. J Mol Biol 131:839–853

    Article  CAS  PubMed  Google Scholar 

  • Wegner A (1980) The interaction of alpha, alpha- and alpha, beta-tropomyosin with actin filaments. FEBS Lett 119:245–248

    Article  CAS  PubMed  Google Scholar 

  • Weigt C, Wegner A, Koch MH (1991) Rate and mechanism of the assembly of tropomyosin with actin filaments. Biochemistry 30:10700–10707

    Article  CAS  PubMed  Google Scholar 

  • Xu C, Craig R, Tobacman L, Horowitz R, Lehman W (1999) Tropomyosin positions in regulated thin filaments revealed by cryoelectron microscopy. Biophys J 77:985–992

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This work has been supported by a grant from the British Heart Foundation (PG/06/055).

Author information

Authors and Affiliations

  1. Department of Biochemistry, Faculty of Medicine and Biological Sciences, University of Leicester, Henry Wellcome Building, Lancaster Road, Leicester, LE1 9HN, UK

    Mohammed El-Mezgueldi

Authors
  1. Mohammed El-Mezgueldi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mohammed El-Mezgueldi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

El-Mezgueldi, M. Tropomyosin dynamics. J Muscle Res Cell Motil 35, 203–210 (2014). https://doi.org/10.1007/s10974-014-9377-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10974-014-9377-x

Keywords

Search

Navigation