B.S., Biology, Seoul National University, Seoul, Korea
M.S., Biophysics, Seoul National University, Seoul, Korea
Ph.D., Biophysics, University of California, Berkeley
Postdoctoral fellow, Cornell University and University of California, Los Angeles
Professor Senyon Choe joined the Salk Institute in 1993 as the first member of the Institute's newly initiated Structural Biology Laboratory. Choe uses X-ray crystallography as a major tool to determine three-dimensional structures of biologically important molecules. He and his colleagues also study the relationship between a molecule's fine structure and the functions it carries out.
Among Choe's recent interests is the study of molecules that bind to specific cells to instruct them to carry out functions. An extension of this work will explore the possibility of designing new molecules that can be delivered specifically to modulate sick cells. His group also has done pioneering work on the molecular structure of an ion channel, important to many physiological functions ranging from heart rate to nerve cell communication.
"Biological messages are written and delivered between cells by
messenger molecules in the body. The two messenger systems we
are focusing on are called ion channels (for e-mails) and protein
hormone receptors (for snail mail). By visualizing these messengers
to better understand how such messages are coded for specific
delivery, we can create brand-new messages of our own."
The premise that "form follows function"
became a mantra for numerous leading
architects and industrial designers during a
good part of the last century. In biology,
evolution operates according to a similar
premise because forms with better functionality
are likelier to be selected. Trying
to understand the relationship between a
molecule's fine structure and the functions
it carries out, Choe and his colleagues use
x-ray crystallography and NMR spectroscopy
to zoom in on ion channels and receptors in
the cell membrane to visualize how they interact
with messenger proteins. Recent work
focused on analyzing the three-dimensional
structure of a whole protein complex to illustrate
how TGF-beta, a messenger molecule
that plays a role in cancer, the immune
system and heart disease, binds to its receptor
molecules on specific target cells to
instruct them to do its bidding. An extension
of this work explores the possibility of designing
new messages to instruct cells to carry
out non-natural processes such as coaxing
differentiated cells back into an immature,
pluripotent state. These types of newly created
messages will have tremendous clinical
potential as guiding molecules.
Human integral membrane proteins (hIMPs)
are attached to the membrane surrounding
each cell, serving as gateways for absorbing
nutrients, hormones and drugs; removing
waste products; and allowing cells to communicate
with their environment. Many
diseases, including Alzheimer's, heart disease
and cancer, have been linked to malfunctioning
hIMPs, and many drugs, ranging
from aspirin to schizophrenia medications,
target these proteins. These receptors and
ion channels are extremely hard to produce
and hence notoriously difficult to study, but
Choe's group recently developed a new technique
for rapidly determining their structure.
Knowing the exact three-dimensional shape
of hIMPs allows drug developers to understand
the precise biochemical mechanisms
by which current drugs work and to develop
new drugs that target the proteins.
Awards and Honors
- Klingenstein Fellowship Award in Neurosciences, 1997
- AAAS Fellow, 1999
Choe, S., Bennett, M., Fujii, G., Curmi, P.A.M., Kantardjieff, K.A., Collier, R.J., Eisenberg, D. (1992) Three domains for three functions: The crystal structure of diphtheria toxin. Nature 357, 216-222.
Lovejoy, B., Choe, S., Cascio, D., McRorie, D.K., DeGrado, W.F., Eisenberg, D. (1993) Crystal structure of a synthetic triple-stranded alpha-helical bundle. Science 259, 1288-1293.
Bennett, M., Choe, S., Eisenberg, D. (1994) Domain Swapping: Proteins in entangled alliances, Proc. Natl. Acad. Sci. 91, 3127-3131.
Choe, S., Stevens, C.F., Sullivan, J.M. (1995) Three distinct structural environments of a transmembrane domain of the inwardly rectifying potassium channel defined by perturbation. Proc. Natl. Acad. Sci. USA 92, 12046-12049.
Louie, G., Yang, W., Bowman, M., Choe, S. (1997) Crystal structure of diphtheria toxin in complex with an extracellular fragment of its receptor, Molecular Cell 1, 67-78.
Kreusch, A., Pfaffinger, P., Stevens, C.F., Choe, S. (1998) Crystal structure of the tetramerization domain of the Shaker potassium channel. Nature 392, 945-8.
Choe, S., Robinson, R. (1998) An ingenious filter: the structural basis of ion selectivity. Neuron 20, 821-3.
Ryan, A., Blumberg, B., Rodriguez-Estaban, C., Yonie-Tamura, S., Tamura, K., Tsukui, T., Peña, J., Sabbagh, W., Greenwald, J., Choe, S., Norris, D.P., Robertson, E.J., Evans, R.M., Rosenfeld, M.G., Belmonte, J. (1998) Pitx2 determines left-right asymmetry of internal organs in vertebrates. Nature 394, 545-51.
Greenwald, J., Fischer, W., Vale, W.W., Choe, S. (1999) Three finger toxin fold for the extracellular ligand-binding domain of type II activin receptor kinase. Nature Struc. Biol. 6, 18-22.
Bixby, K., Nanao, M., Shen, V., Kreusch, A., Bellamy, H., Pfaffinger, P., Choe, S. (1999) Zn2+-mediated and molecular determinants of tetramerization in voltage-gated K+ channels. Nature Struc. Biol., 6, 38-43.
Robinson, R., Mejilano, M., Le, V., Burtnick, L.D., Yin, H.L., Choe, S. (1999) Domain movement in gelsolin: a Ca-activated switch. Science, 286, 1939-1942.
Cushman, S.J., Nanao, M.H., Jahng, A.W., DeRubeis, D., Choe, S., Pfaffinger, P.J. (2000) Voltage-dependent activation of potassium channels is coupled to T1 domain structure. Nature Struc. Biol., 7, 403-407.
Robinson, R., Choe, S., Burtnick, L.D. (2001) Disintegration of actin filaments: a role of gelsolin. Proc. Natl. Acad. Sci., 98, 2117-2118.
Zhou, W., Arrabit, C., Choe, S., Slesinger, P. (2001) Bupivacaine inhibits ethanol- and G protein-gated inwardly rectifying K channels. Proc. N. A. S., 98, 6482-7.
Robinson, R., Turbedsky, K., Kaiser, D., Higgs, H.N., Marchand, J., Choe, S., Pollard, T.D. (2001) Crystal structure of Arp2/3 complex. Science, 294, 1679-84.
Choe, S. (2002) Potassium Channel Structures. Nature Reviews Neurosci., 3, 115-121.
Roosild, T., Miller, S., Booth, I., Choe, S. (2002) A mechanism of regulation for potassium flux mediated by conformational change. Cell, 109, 781-791.
Groppe, J., Greenwald, J., Wiater, E., Rodriguez-Leon, J., Economides, A., Kwaitkowski, W., Affolter, M., Vale, W., I.-Belmonte, J.-C., Choe, S. (2002) Structural basis of BMP signaling inhibition by Noggin, a novel cystine knot protein. Nature, 420, 636-642.
Greenwald, J., Groppe, J., Gray, P., Wiater, E., Kwiatkowski, W., Vale, W., Choe, S.. (2003) The BMP7/ActRII extracellular domain complex provides new insights into the cooperative nature of receptor assembly. Molecular Cell, 11, 605-17.
Zhou, W., Qian, Y., Kunjilwar, K., Pfaffinger, P.J., Choe, S. (2004) Structural Insights into the Functional Interaction of KChIP1 with Shal-Type K+ Channels. Neuron 41, 573-586.
Greenwald, J., Vega, M., Allendorph, G., Fischer, W., Vale, W., Choe, S. (2004) A flexible activin explains the membrane-dependent cooperative assembly of TGF-beta family receptors. Molecular Cell, 15, 485-9
Roosild, T.P., Greenwald, J., Vega, M., Castronovo, S., Riek, R., and Choe, S. (2005) NMR Structure of Mistic, a Membrane-Integrating Protein for Membrane Protein Expression Science 307,1317-21.
Pegan, S., Arrabit, C., Zhou, W., Kwiatkowski, W., Collins, A., Slesinger, P., Choe, S. (2005) Cytoplasmic domain structures of Kir2.1 and Kir3.1 show sites for modulating gating and rectification. Nature Neuroscience. 8, 279-287.
Allendorph, G., Vale, W.W., Choe, S. (2006) Structure of the ternary signaling complex of a TGF-b superfamily member. Proc. Natl. Acad. Sci., 103, 7643-8.
Kuo, M. M-C., Baker, K.A., Wong, L., Choe, S. (2007) Dynamic oligomeric conversions of the cytoplasmic RCK domains mediate MthK potassium channel activity. Proc. Natl. Acad. Sci. 104, 2151-6.
Maslennikov, I., Klammt, C., Hwang, E., Kefala, G., Okamura, M., Esquivies, L., Mors, K., Glaubitz, C., Kwiatkowski, W., Jeon Y.H., Choe, S. (2010) Membrane domain structures of three classes of histidine kinase receptors by cell-free expression and rapid NMR analysis. Proc. Natl. Acad. Sci. USA, 107, 10902-7.
Allendorph, G., Read, J.D., Kawakami, Y., Kelber, J.A., Isaacs, M.J., Choe, S. (2011) Designer TGF-beta superfamily ligands with diversified functionality. PLoS One, 6, e26402.
Farina, A.N., Blain, K.Y., Maruo, T., Kwiatkowski, W., Choe, S., Nakagawa, T. (2011) Separation of domain contacts is required for heterotetrameric assembly of functional NMDA receptors. J. Neurosci. 31: 3565-79.
Balana, B., Maslennikov, I., Kwiatkowski, W., Stern, K.M., Bahima, L., Choe, S., Slesinger, P.A. (2011) Mechanism underlying selective regulation of G protein-gated inwardly rectifying potassium channels by the psychostimulant-sensitive sorting nexin 27. Proc. Natl. Acad. Sci. 108: 5831-6.
Klammt, C., Maslennikov, I., Bayrhuber, M., Eichmann, C., Vajpai, N., Chiu, E.J.C., Blain, K., Esquivies, L., Kwon, J.H.J., Balana, B., Pieper, U., Sali, A., Slesinger, P., Kwiatkowski, W., Riek, R., Choe, S. (2012) Facile NMR structure determination of human membrane proteins. Nature Methods, 9, 834-9.
Ou, H.D., Kwiatkowski, W., Deerinck, T., Noske, A., Blain, K.Y., Land, H., Soria, C., Powers, C.J., Shu, X., Tsien, R., Fitzpatrick, J.A.J., Long, J.A., Ellisman, M.H., Choe,S., O'Shea, C.C. (2012) Structure of E4-ORF3 reveals a viral supramolecular assembly that inactivates multiple tumor suppressors. Cell, 151, 304-19.
Salk News Releases
- Speeding up drug discovery with rapid 3D mapping of proteins, May 29, 2012
- Salk scientists crack molecular code regulating neuronal excitability, March 21, 2011
- Site for alcohol's action in the brain discovered, June 28, 2009
- Elastic Gateway in Ion Channel Discovered, March 24, 2005
- 'Mistic' Breakthrough in Membrane Science, February 24, 2005
- Structure of Molecular Scissors Critical for the Shaping of Cells Revealed by Structural Biologists at The Salk Institute, December 2, 1999
- Zinc Found To Be Integral Part Of Brain Communication Channels, January 6, 1999
© Salk Institute for Biological Studies
10010 North Torrey Pines Road, La Jolla, CA 92037 | 858.453.4100