Characterization of the actomyosin binding interface
Final Report Abstract
Filamentous actin can exist in multiple conformations depending on the type of bound nucleotide and the isoform of actin. Accordingly, even closely related myosin and actin should show isoform-specific differences in their functional interactions. We tested this hypothesis for several human myosin isoforms. We characterized the extent to which actin filaments formed from α-actin, β-actin, and γ-actin display differences in their ability to activate the ATPase activity and support the motility of these myosins. We focused in particular on the interaction of human myosin isoforms that show much larger differences in their ability to productively interact with F-actin formed from β-actin and γ-actin than can be observed with fast skeletal muscle myosin-2 isoforms. Distinct functional interactions between the actin isoforms and nonsarcomeric myosins were revealed and the consequences of human alpha-cardiac actin mutations Y166C and M305L that lead to familial hypertrophic cardiomyopathy were characterized in detail. In addition to the elucidation of a wide range of functional changes, we determined structural features of human myosin isoforms and of the actomyosin binding interface in the presence of tropomyosin. Key results that were derived from our work on actomyosin are summarized in a review article. In this review article, we also discuss the potential of myosin as a drug target on the background of structural insights obtained in the context of FOR 629 and how these insights can be translated into drugs discriminating between myosin isoforms.
Publications
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(2010) Targeted optimization of a protein nanomachine for operation in biohybrid devices. Angew Chem Int Ed Engl 49: 312-316
Amrute-Nayak M, Diensthuber RP, Steffen W, Kathmann D, Hartmann FK, Fedorov R, Urbanke C, Manstein DJ, Brenner B, Tsiavaliaris G
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(2011) Actin as target for modification by bacterial protein toxins. FEBS J. 278, 1-18
Aktories, K., Lang, A.E., Schwan, C., and Mannherz, H.G.
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(2011) Actin: From structural plasticity to functional diversity. Eur. J. Cell Biol. 90, 797-804
Schoenenberger, C.A., Mannherz, H.G., and Jockusch, B.M.
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(2011) Comparative kinetic and functional characterization of the motor domains of human nonmuscle myosin-2C isoforms. J Biol Chem 286: 21191-21202
Heissler SM, Manstein DJ
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(2011) Inhibition of Myosin ATPase Activity by Halogenated Pseudilins: A Structure-Activity Study. J Med Chem 54: 3675-3685
Preller M., Chinthalapudi K., Martin R., Knölker H.-J., Manstein D.J.
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(2011) Mechanism and specificity of pentachloropseudilin-mediated inhibition of myosin motor activity. J Biol Chem 286: 29700-29708
Chinthalapudi K, Taft MH, Martin R, Heissler SM, Preller M, Hartmann FK, Brandstaetter H, Kendrick- Jones J, Tsiavaliaris G, Gutzeit HO, Fedorov R, Buss F, Knölker H-J, Coluccio LM, Manstein DJ
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(2011) Phalloidin perturbs the interaction of human non-muscle myosin isoforms 2A and 2C1 with F-actin. FEBS Lett 585: 767-771
Diensthuber R.P., Müller M., Heissler S.M., Taft M.H., Chizhov I., and Manstein D.J.
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(2012) An antiparallel actin dimer is associated with the endocytic pathway in mammalian cells. J. Struct. Biol. 177, 70-80
Silvan, U., Boiteux, C., Sütterlin, R., Schroeder, U., Mannherz, H.G., Jockusch, B.M., Bernèche, S., Aebi, U., and Schoenenberger, C.A.
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(2012) Functional characterization of the human alpha-cardiac actin mutations Y166C and M305L involved in hypertrophic cardiomyopathy. Cell Mol Life Sci 69: 3457-3479
Müller M, Mazur AJ, Behrmann E, Diensthuber RP, Radke MB, Qu Z, Littwitz C, Raunser S, Schoenenberger CA, Manstein DJ, Mannherz HG
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(2012) Functional characterization of the human myosin-7a motor domain. Cell Mol Life Sci 69: 299-311
Heissler SM, Manstein DJ
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(2012) Kinetic properties and small-molecule inhibition of human myosin-6. FEBS Lett 586: 3208-3214
Heissler SM, Selvadurai J, Bond LM, Fedorov R, Kendrick-Jones J, Buss F, and Manstein DJ
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(2012) Myosin Motors: Structural Aspects and Functionality (Chapter 4.8). In Comprehensive Biophysics, Editor-in-Chief: Edward H.E. (ed.), pp 118-150. Amsterdam: Elsevier. ISBN: 978-0-08-095718-0
Preller M. and Manstein D.J.
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(2012) Subnanometer-Resolution Structure of the Rigor Actin-Tropomyosin-Myosin Complex Cell 150: 327-338
Behrmann E, Müller M, Penczek PA, Mannherz HG, Manstein DJ, and Raunser S
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(2013) Distinct functional interactions between actin isoforms and nonsarcomeric myosins. PLoS One 8: e70636
Müller M, Diensthuber RP, Chizhov I, Claus P, Heissler SM, Preller M, Taft MH, and Manstein DJ
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(2013) Myosin structure, allostery, and mechano-chemistry. Structure 21: 1911-1922
Preller M. and Manstein D.J.
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(2013) Nonmuscle myosin-2: mix and match. Cell Mol Life Sci 70: 1-21
Heissler S.M. and Manstein D.J.
