derosier

Andrew Szent-Györgyi, M.D
Professor of Biology, Emeritus

Regulation of Muscle Function

M.D., University of Budapest

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We are interested in the mechanism of how muscle function is controlled at the molecular level. Muscle contraction is the result of repetitive cyclic interactions of two proteins, actin and myosin. The resting state of muscle is maintained by regulatory proteins which prevent this interaction. Calcium triggers contraction by binding to the regulatory proteins, and reversing their inhibitory function. Contraction may be inhibited by regulatory components that block sites on actin or by components that block sites on myosin. Myosin linked regulation was discovered in our laboratory and involves both small subunits of myosin, the regulatory and the essential light chains. This type of regulation is widely distributed in invertebrates, and a variant of it operates also in the smooth muscles of vertebrates. The best system for the study of myosin based control is the striated muscle of the scallop, since the regulatory light chains can be removed from, and readded to scallop myosin. In the absence of regulatory light chains, the muscle can contract but is unable to relax. When regulatory light chains are readded, control is fully restored and the calcium dependency of contractile functions, such as ATPase activity and tension development, is regained.

We are employing chemical and genetic modifications to characterize the "on" and "off" state of muscle and to follow the structural rearrangement the subunits undergo when the muscle is triggered into activity. We have isolated from myosin a small fragment that binds both light chains and retains the triggering calcium binding sites. This regulatory complex has been crystallized and its structure determined in Prof. Carolyn Cohen's laboratory. With site directed mutagenesis we alter specific residues of the light chains and the heavy chain of myosin to identify those amino acid residues and peptide sequences that are responsible for various aspects of regulatory functions such as calcium binding, interactions of light and heavy chains of myosin, inhibition of contractile activity and the location of the light chains on myosin.

The combined approaches of structural studies and in vitro mutagenesis help us to clarify the molecular events responsible for the resting and active states of muscle.

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Selected Publications:

Crystal structure of a phosphorylated light chain domain of scallop smooth-muscle Myosin. Senthil Kumar VS, O'Neall-Hennessey E, Reshetnikova L, Brown JH, Robinson H, Szent-Györgyi AG, Cohen C. Biophys J. 2011 Nov 2;101:2185-9. [abstract]

Visualizing key hinges and a potential major source of compliance in the lever arm of myosin. Brown JH, Kumar VS, O'Neall-Hennessey E, Reshetnikova L, Robinson H, Nguyen-McCarty M, Szent-Györgyi AG, Cohen C. Proc Natl Acad Sci U S A. 2011 Jan 4;108:114-9. [abstract]

Myosin cleft closure determines the energetics of the actomyosin interaction.Takács B, O'Neall-Hennessey E, Hetényi C, Kardos J, Szent-Györgyi AG, Kovács M. FASEB J. 2011 Jan; 25:111-21. [abstract]

The ultrastructure and contractile properties of a fast-acting, obliquely striated, myosin-regulated muscle: the funnel retractor of squids.Rosenbluth J, Szent-Györgyi AG, Thompson JT. J Exp Biol. 2010 Jul 15; 213(Pt 14):2430-43. [abstract]

The on-off switch in regulated myosins: different triggers but related mechanisms.Himmel DM, Mui S, O'Neall-Hennessey E, Szent-Györgyi AG, Cohen C. J Mol Biol. 2009 Dec 4;394:496-505. [abstract]

Rigor-like structures from muscle myosins reveal key mechanical elements in the transduction pathways of this allosteric motor. Yang Y, Gourinath S, Kovács M, Nyitray L, Reutzel R, Himmel DM, O'Neall-Hennessey E, Reshetnikova L, Szent-Györgyi AG, Brown JH, Cohen C. Structure. 2007 May;15:553-64. [abstract]

Regulation by myosin: how calcium regulates some myosins, past and present.Szent-Györgyi AG. Adv Exp Med Biol. 2007;592:253-64

Dipesh Risal, S. Gourinath, Daniel M .Himmel, Andrew G. Szent-Györgyi and Carolyn Cohen. (2004). Myosin subfragment 1 structures reveal a partially bound nucleotide and a complex salt bridge that helps couple nucleotide and actin binding. Proc. Natl. Acad. Sci. USA 101: 8930-6935. [abstract]

Andrew G. Szent-Györgyi (2004). Milestone in Physiology: The Early History of the Biochemistry of Muscle Contraction. J. Gen. Physiol. 123: 631-641.

Gourinath S, Himmel DM, Brown JH, Reshetnikova L, Szent-Gyorgyi AG, Cohen C. (2003) Crystal structure of scallop myosin S1 in the pre-power stroke state to 2.6 a resolution: flexibility and function in the head. Structure. 11:1621-7. [abstract]

Nyitrai M, Stafford WF, Szent-Gyorgyi AG, Geeves MA. (2003) Ionic interactions play a role in the regulatory mechanism of scallop heavy meromyosin. Biophys J. 85:1053-62. [abstract]

Nitao LK, Loo RR, O'Neall-Hennessey E, Loo JA, Szent-Gyorgyi AG, Reisler E. (2003) Conformation and dynamics of the SH1-SH2 helix in scallop myosin. Biochemistry. 42:7663-74. [abstract]

Nyitrai M, Szent-Gyorgyi AG, Geeves MA. (2003) Interactions of the two heads of scallop (Argopecten irradians) heavy meromyosin with actin: influence of calcium and nucleotides. Biochem J. 370(Pt 3):839-48. [abstract]

Himmel DM, Gourinath S, Reshetnikova L, Shen Y, Szent-Gyorgyi AG, Cohen C. (2002) Crystallographic findings on the internally uncoupled and near-rigor states of myosin: further insights into the mechanics of the motor. Proc Natl Acad Sci U S A. 99:12645-50. [abstract]

Nyitrai M, Szent-Gyorgyi AG, Geeves MA. (2002) A kinetic model of the co-operative binding of calcium and ADP to scallop (Argopecten irradians) heavy meromyosin. Biochem J. 365(Pt 1):19-30.[abstract]

Stafford WF, Jacobsen MP, Woodhead J, Craig R, O'Neall-Hennessey E, Szent-Gyorgyi AG. (2001) Calcium-dependent structural changes in scallop heavy meromyosin. J Mol Biol. 307:137-47. [abstract]

Houdusse A, Szent-Gyorgyi AG, Cohen C. (2000) Three conformational states of scallop myosin S1. Proc Natl Acad Sci U S A. 97:11238-43. [abstract]

Houdusse A, Kalabokis VN, Himmel D, Szent-Gyorgyi AG, Cohen C. (1999) Atomic structure of scallop myosin subfragment S1 complexed with MgADP: a novel conformation of the myosin head. Cell. 97:459-70. [abstract]

Szent-Gyorgyi AG, Kalabokis VN, Perreault-Micale CL. (1999) Regulation by molluscan myosins. Mol Cell Biochem. 190:55-62. [abstract]

Kalabokis VN, Szent-Gyorgyi AG. (1998) Regulation of scallop myosin by calcium. Cooperativity and the "off" state. Adv Exp Med Biol. 453:235-40. [abstract]

Matulef K, Sirokman K, Perreault-Micale CL, Szent-Gyorgyi AG. (1998) Amino-acid sequence of squid myosin heavy chain. J Muscle Res Cell Motil. 19:705-12. [abstract]

Kalabokis VN, Szent-Gyorgyi AG. (1997) Cooperativity and regulation of scallop myosin and myosin fragments. Biochemistry. 36:15834-40. [abstract]

Kalabokis, V.N., Vibert, P., York, M.L., Szent-Györgyi, A.G. (1996). Single-headed scallop myosin and regulation. J. Biol. Chem. 271:26779-26782. [abstract] [full text]

Perreault-Micale, C.L., Kalabokis, V., Nyitray, L. and Szent-Györgyi, A.G. (1996). Sequence variations in the surface loop near the nucleotide binding site modulate the ATP turnover rates of molluscan myosins. J. Muscle Res. Cell Motil. 17:543-553. [abstract]

Perreault-Micale, C.L., Jancso, A. and Szent-Györgyi, A.G. Essential and regulatory light chains of Placopecten striated and catch muscle myosins. (1996). J. Muscle Res. Cell Motil. 17:533-542. [abstract]

Szent-Györgyi, A.G. (1996). Regulation of Contraction by Calcium Binding Myosins. Biophysical Chemistry 59:357-363. [abstract]

Szent-Györgyi, A.G., Fromherz, S., Jansco, A., Nyitray, L., and Kalabokis, V.N. (1995). Regulation of Muscle Contraction by a Calcium-Binding Myosin: Structural and Mutational Studies. In Calcium as Cell Signal, Proceedings of the Yamada Conference XXXIX, pp. 65-72, Igaku-Shoin Ltd., Tokyo.

Fromherz, S and Szent-Györgyi, A.G. (1995). Role of essential light chain EF hand domains in calcium binding and regulation of scallop myosin. Proc. Natl. Acad. Sci. USA 92: 7652-7656. [abstract]

Nyitray, L., Jancso, A., Ochiai, O., Graf, L. and Szent-Györgyi, A.G. (1994). Scallop striated and smooth muscle myosin heavy-chain isoforms are produced by alternative RNA splicing from a single gene. Proc. Natl. Acad. Sci. USA 91: 12686-12690. [abstract]

Kalabokis, V.N., O'Neall-Hennessey, E. and Szent-Györgyi, A.G.. (1994). Regulatory Domains of Myosins: Influence of Heavy Chain on Calcium Binding. J. Mus. Res. Cell Motil. 15: 547-5533. [abstract]

Jancso, A. and Szent-Györgyi, A.G. (1994). Regulation of Scallop Myosin by the Regulatory Light Chain Depends on a Single Glycine Residue. Proc. Natl. Acad. Sci. USA, 91: 8762-8766. [abstract]

Xie, X., Harrison, D.H., Schlichting, I., Sweet, R.M., Kalabokis, V.N., Szent-Györgyi, A.G. and Cohen, C. (1994). Structure of the Regulatory Domain of Scallop Myosin at 2.8Ä Resolution. Nature 368: 306-312. [abstract] [structure info]


Last review: November 21, 2011.

 

 
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