Carolyn Cohen

Carolyn Cohen, Ph.D.
Professor Emeritus of Biology
Rosenstiel Basic Medical Sciences Research Center

Member, US National Academy of Sciences

Protein Structure, Dynamics, and Assembly

Ph.D., Massachusetts Institute of Technology

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Our major objective is to determine the precise molecular architecture of certain a-proteins that have dynamic as well as structural roles in the cell. The chief methods are X-ray crystallography together with molecular biology and biochemistry. Muscle proteins are a central focus and provide the background for studying related systems. Myosin is the fundamental protein involved in muscle contraction. We seek to visualize in atomic detail how this motor works by obtaining "snapshots" of the molecule in different stages of contraction. This motor is switched "on" and "off" by calcium ions which bind to regulatory proteins such as tropomyosin/troponin and - in certain cases - to myosin itself. Atomic structures of these switches are being sought to see how the motor activity is controlled. The molecular basis of blood clotting is being studied by a similar approach: the crystal structure of fibrinogen or key subfragments is being determined by X-ray crystallography in order to understand its assembly into the fibrin clot.

We are also working on the protein folding problem. The a-helical coiled-coil motif has been shown to have a widespread occurrence in a diverse range of proteins, including those in muscle (myosin rod, tropomyosin, paramyosin), membranes, and transcription factors (leucine zipper). The fact that this motif may be recognized easily and directly in the amino acid sequence of a protein through the presence of a seven-residue "heptad" repeat gives it special significance. This simple example of pattern recognition is an important first step in solving structures from sequence data alone. A key part of our studies focuses on sequence features that determine whether two helices are likely to be parallel or antiparallel, how special stability or flexibility may be achieved, and how one might approach the design of a number of different proteins including parallel two-chain coiled coils, 4-a-helix bundles, and membrane proteins. By making as many connections as possible among apparently diverse protein classes, we hope to establish some of the physical principles underlying protein folding.

Dr. Cohen is a Member of the National Academy of Sciences and a Fellow of the American Academy of Arts and Sciences. She received the 2000 Founder's Award for outstanding achievement in Biophysics from the Biophysical Society.

Selected Publications:

Cohen C. Mrs. Professor. J Biol Chem. 2011 Jul 28. [abstract]

Brown JH, Kumar VS, O'Neall-Hennessey E, Reshetnikova L, Robinson H, Nguyen-McCarty M, Szent-Györgyi AG, Cohen C. Visualizing key hinges and a potential major source of compliance in the lever arm of myosin. Proc Natl Acad Sci U S A. 2011 Jan 4;108(1):114-9. Epub 2010 Dec 13.[abstract]

Himmel, D.M., Mui, S., O'Neall-Hennessey, E., Szent-Gyorgyi, A.G. and Cohen, C. The on-off switch in regulated myosins: different triggers but related mechanisms. J. Mol. Biol. 394: 496-505 (2009). [abstract]

Brown JH, Yang Y, Reshetnikova L, Gourinath S, Süveges D, Kardos J, Hóbor F, Reutzel R, Nyitray L, Cohen C. (2008) An unstable head-rod junction may promote folding into the compact off-state conformation of regulated myosins. J Mol Biol. 2008 Feb 1; 375:1434-43. [abstract]

Cohen, C.  (2007).  Reflections:  Seeing and knowing in structural biology.  J. Biol. Chem. 282: 32529-32538. [abstract]

Yuting, Y., Gourinath, S., Kovács, M., Nyitray, L., Reutzel, R., Himmel, D., O'Neal-Hennessey, E., Reshetnikova, L., Szent-Györgyi, A., Brown, J. and Cohen, C. (2007).  Rigor-like structures from muscle myosins reveal key mechanical elements in the transduction pathways of this allosteric motor.  Structure 15: 553-564. [abstract]

Brown, J. H., Zhou, Z., Reshetnikova, L., Robinson, H., Yammani, R., Tobacman, L.S., and Cohen, C. The structure of tropomyosin's mid-region: bending and binding sites for actin. (2005) 102:18878-83. [abstract]

Brown, J. H. and Cohen, C. The Structure and Function of Tropmyosin and Troponin, in Fibrous Proteins and Related Structures, Part A, Squire and Parry, eds. Elsevier (2005). Volume 71 in the Advances in Protein Chemistry series.

Risal, D., Gourinath, S., Himmel, D. M., Szent-Gyorgyi, A. G., and Cohen, C. (2004). Myosin S1 structures reveal a novel nucleotide conformation and a complex salt bridge that helps couple nucleotide and actin binding. Proc Natl Acad Sci U S A 101: 8930-5. [abstract]

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 (Camb). 11:1621-7. [abstract]

Li,Y., Brown, J.H., Reshetnikova, L., Blazsek, A. , Farkas, L., Nyitray, L.,and Cohen, C. (2003) Visualization of an unstable coiled coil from the scallop myosin rod. Nature 424:341-345. [abstract]

Himmel, D., Gourinath, S., Reshetnikova, L., Shen, Y., Szent-Gyorgyi, A., and Cohen, C. Crystallographic findings on the internally uncoupled and near-rigor states of myosin: Further insights into the mechanics of the motor. PNAS 99:12645-12650 (2002). [abstract]

Li, Y., Mui, S., Brown, J.H., Strand, J., Reshetnikova, L., Tobacman, L., and Cohen, C. The crystal structure of the C-terminal fragment of striated-muscle a-tropomyosin reveals a key troponin T recognition site. PNAS 99: 7378-7383 (2002). [abstract]

Madrazo, J., Brown, J.H., Litvinovich, S., Dominguez, R., Yakovlev, S., Medved., L., and Cohen, C. Crystal structure of the central region of bovine fibrinogen (E5 fragment) at 1.4 Å resolution. PNAS 98: 11967-11972 (2001). [abstract]

Brown, J., Kim, K-H., Jun, G., Greenfield, N., Dominguez, R., Wolkmann, N., Hitchcock-DeGregori, S., and Cohen, C. Deciphering the design of the tropomyosin molecule. PNAS 98: 8496-8501 (2001). [abstract]

Brown, J.H., Kim, K.-H., Jun, G., Greenfield, N.J., Dominguez, R., Volkmann, N., Hitchcock-DeGregori, S.E. and C. Cohen. 2001. Deciphering the design of the tropomyosin molecule. Proc Natl Acad Sci 98:8496-8501. [abstract at PNAS] [full text at PNAS]

Houdusse, A., Szent-Gyorgyi, A.G., and Cohen, C. 2000. Three conformational states of scallop myosin S1. Proc Natl Acad Sci 97: 11238-11243. [abstract]

Brown, J., Volkmann, N., Jun, G., Henschen-Edman, A., and Cohen, C. 2000. The crystal structure of modified bovine fibrinogen. Proc Natl Acad Sci 97: 85-90. [abstract]

Houdusse, A., Kalabokis, V.N., Himmel, D., Szent-Györgyi, A.G. and C. Cohen. 1999. Atomic structure of scallop myosin subfragment S1 complexed with MgADP: A novel conformation of the myosin head. Cell 97:459-470. [abstract]

Cohen, C. 1998. Why Fibrous Proteins are Romantic. J. Struct. Biol. 122:3-16. [abstract]

Dominguez, R., Freyzon, Y., Trybus, K.M. and Cohen, C. 1998. Crystal structure of a vertebrate smooth muscle myosin motor domain and its complex with the essential light chain: Visualization of the pre-power stroke state. Cell 94: 559-571. [abstract]

Houdusse, A., Love, M.L., Dominguez, R., Grabarek, Z. and Cohen, C. 1997. Structures of four Ca2+-bound troponin C at 2.0 Å resolution: further insights into the Ca2+-switch in the calmodulin superfamily. Structure 5:1695-1711. [abstract]

Houdusse, A., Silver, M. and Cohen, C. 1996. A model of Ca2+-free calmodulin binding to unconventional myosins reveals how calmodulin acts as a regulatory switch. Structure 4: 1475-1490. [abstract]

Brown, J., Cohen, C. and Parry, D.A.D. 1996. Heptad breaks in a-helical coiled coils: Stutters and stammers. Proteins 26, 134-145. [abstract]

Houdusse, A. and Cohen, C. 1996. Structure of the regulatory domain of scallop myosin at 2 Å resolution: Implications for regulation. Structure 4: 21-32. [abstract]

Houdusse, A. and Cohen, C. 1995. Target sequence recognition by the calmodulin superfamily: Implications from light chain binding to the regulatory domain of scallop myosin. Proc. Natl. Acad. Sci. USA 92, 10644-10647. [abstract]

Xie, X., Harrison, D.H., Schlichting, I., Sweet, R., Kalabokis, V.N., Szent-Györgyi, A.G. and Cohen, C. 1994. Structure of the regulatory domain of scallop myosin at 2.8 Å resolution. Nature 368: 306-312. [abstract]

Xie, X., S. Rao, P. Walian, V. Hatch, G.N. Phillips Jr., and C. Cohen. 1994. Coiled-coil packing in spermine-induced tropomyosin crystals: A comparative study of three forms. J. Mol. Biol. 236: 1212-1226. [abstract]

Cohen, C., and Parry, D.A.D. 1994. a-Helical coiled coils: More facts and better predictions. Science 263: 488-489. [abstract]

 

 


Last review: August 8, 2011
 
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