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