Sarah Hitchcock-DeGregori Professor UMDNJ Department of Neuroscience and Cell Biology Robert Wood Johnson Medical School Room 331 Piscataway. NJ 08854 (732) 235-4528 FAX - 4029 hitchcoc@umdnj.edu

Actin cytoskeleton. coiled coils. protein structure. protein structure-function relationships. contractile and motile function

Molecular mechanisms of function and regulation of the actin cytoskeleton

The actin cytoskeleton underlies nearly every fundamental cellular activity including determination and maintenance of cell shape. intracellular architecture and tissue formation. transport of organelles within the cell and movement of the cells themselves. as well as intracellular and cellular signaling. Long-standing. and continuing biochemical and biophysical research has come together with more recent cellular and genetic experiments to show that tropomyosin is a major cellular regulator of actin filament stability and binding of other proteins to actin that modulate its function. Our goal is to understand the molecular mechanisms underlying the regulation of actin filament contractile and motile function. Research projects range from biophysics and biochemistry to cell biology: Current work includes (1) determination of structures of functional fragments of tropomyosin and tropomyosin binding proteins at atomic resolution using heteronuclear NMR (the work of Dr. Norma Greenfield). (2) analysis of the importance of flexibility for function in coiled coil cytoskeletal proteins. (3) study of the regulation of actin dynamics by proteins that bind to actin including tropomyosin. tropomodulin. and the Arp2/3 complex. and (4) experiments to understand the function of specific tropomyosin isoforms in cells.

Selected Publications

Singh A, Hitchcock-Degregori SE. (2009) A peek into tropomyosin binding and unfolding on the actin filament. PLoS One. 4(7):e6336.

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

Greenfield NJ, Kotlyanskaya L, Hitchcock-Degregori SE. (2009) Structure of the N Terminus of a Nonmuscle alpha-Tropomyosin in Complex with the C Terminus: Implications for Actin Binding (dagger) (double dagger). Biochemistry. Jan 26. [Epub ahead of print]

Singh A, Hitchcock-DeGregori SE. (2007) Tropomyosin's periods are quasi-equivalent for actin binding but have specific regulatory functions. Biochemistry. 46(51):14917-27. Epub 2007 Dec 4.

Kostyukova AS, Hitchcock-Degregori SE, Greenfield NJ. (2007) Molecular basis of tropomyosin binding to tropomodulin, an actin-capping protein. J Mol Biol. 372(3):608-18.

Wawro B, Greenfield NJ, Wear MA, Cooper JA, Higgs HN, Hitchcock-DeGregori SE. (2007)
Tropomyosin regulates elongation by formin at the fast-growing end of the actin filament.
Biochemistry. 46(27):8146-55.

Hitchcock-DeGregori SE, Greenfield NJ, Singh A. (2007) Tropomyosin: regulator of actin filaments. Adv Exp Med Biol. 592:87-97. Review.

Hitchcock-Degregori SE. (2006) Chemotaxis: Cofilin in the driver's seat. Curr Biol. 16(24):R1030-2.

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(1):80-96.

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(1):43-50.

Kostyukova AS. Rapp BA. Choy A. Greenfield NJ. Hitchcock-DeGregori SE. (2005) Structural requirements of tropomodulin for tropomyosin binding and actin filament capping. Biochemistry. Mar 29;44(12):4905-10.

Gupton SL. Anderson KL. Kole TP. Fischer RS. Ponti A. Hitchcock-DeGregori SE. Danuser G. Fowler VM. Wirtz D. Hanein D. Waterman-Storer CM. (2005) Cell migration without a lamellipodium: translation of actin dynamics into cell movement mediated by tropomyosin. J Cell Biol. 168(4):619-31.

Greenfield NJ. Kostyukova AS. Hitchcock-DeGregori SE. (2005) Structure and tropomyosin binding properties of the N-terminal capping domain of tropomodulin 1. Biophys J. 88(1):372-83.

Bharadwaj S. Hitchcock-DeGregori S. Thorburn A. Prasad GL. (2004) N terminus is essential for tropomyosin functions: N-terminal modification disrupts stress fiber organization and abolishes anti-oncogenic effects of tropomyosin-1. J Biol Chem. 279(14):14039-48.

Kostyukova AS. Hitchcock-DeGregori SE. (2004) Effect of the structure of the N terminus of tropomyosin on tropomodulin function. J Biol Chem. 279(7):5066-71.

Singh A. Hitchcock-DeGregori SE. (2003) Local destabilization of the tropomyosin coiled coil gives the molecular flexibility required for actin binding. Biochemistry. 42(48):14114-21.

Hitchcock-DeGregori SE. (2003) Now. swing your partner! 3D-domain switching of WASP activates Arp2/3 complex. Nat Struct Biol. 10(8):583-4.

Palm T. Greenfield NJ. Hitchcock-DeGregori SE. (2003) Tropomyosin ends determine the stability and functionality of overlap and troponin T complexes.Biophys J. 84(5):3181-9.

Greenfield. N.J.. Swapna. G.V.T.. Huang. Y.. Palm. T.. Graboski. S.. Montelione. G.T. and Hitchcock-DeGregori. S.E. (2003) The structure of the carboxyl terminus of striated "-tropomyosin in soilution reveals an unusual parallel arrangement of interacting "-helices. Biochemistry 42: 614-619.