Kyoung Joon Oh, PhD

Biochemistry and Molecular Biology Discipline

Center for Proteomics and Molecular Therapeutics

California Institute of Technology, PhD, 1993
University of California Los Angeles, Postdoc., 1993-1997
Harvard Medical School, Postdoc.,1997-1999
Harvard Medical School, Instructor, 2001-2007
Dana-Farber Cancer Institute, Research Scientist, 1999-2007

Research

Programmed cell death or apoptosis is a genetically programmed physiological process enabling removal of unwanted cells or of cells infected with pathogens.  Consequently, apoptosis is essential for the development and maintenance of tissues in multi-cellular organisms.  Dysregulation of apoptosis can lead to a wide range of diseases including cancer and neurodegenerative diseases.  Elucidation of the signal transduction mechanisms in apoptotic processes at the molecular level could potentially identify therapeutic targets for such diseases. 

An important group of molecules known as the BCL-2 (i.e., B-cell lymphoma-2) family of proteins act as critical regulators of the apoptotic pathways involving intracellular organelles such as mitochondria and the endoplasmic reticulum.  Certain BCL-2 family members, when activated by cell death signals, are known to undergo conformational changes and insert into the mitochondrial membrane and to form pores, thereby resulting in damage to the integrity of mitochondria, the powerhouse of the cell.  Currently, ‘membrane-inserted’ structure is not known for any of the BCL-2 proteins in detail.  Furthermore, signal transduction pathways involving certain BCL-2 family proteins are controversial.

Using various biochemical methods and biophysical methods we aim to delineate the mechanism by which the pore-forming BCL-2 proteins become activated by other pro-apoptotic BCL-2 members and how they are organized within the membrane-pore.  In particular, using a recently developed biophysical method known as the site-directed spin labeling (SDSL) approach of electron paramagnetic resonance (EPR) spectroscopy we are studying the structure of the BCL-2 proteins in the membrane-inserted state.  The detailed structure/function information will provide novel insight that will likely facilitate the identification of drug targets for controlling the apoptotic sequences that occur in many diseases.

Publications

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• Mandal, T., Hustedt E.J., Song, L. and Oh, K.J. 2019. CW EPR and DEER Methods to Determine BCL-2 Family Protein Structure and Interactions: Application of Site-Directed Spin Labeling to BAK Apoptotic Pores. In: Methods in Molecular Biology: BCL-2 Family Proteins Methods and Protocols. Ed. Evripidis Gavathiotis. New York, New York: Humana Press; 2019. vol. 1877, p. 257-303. (medline)
• Mandal, T., Shin, S., Aluvila, S., Chen, H.C., Grieve, C., Choe, J.Y., Cheng, E. H., Hustedt, E. J., Oh, K.J. 2016. Assembly of Bak homodimers into higher order homooligomers in the mitochondrial apoptotic pore. Scientific Reports, Nature Publishing Group, 6: 30763. [Scientific Reports]
• Kim, J.W., Yang. Y.S., Song. S.S., Na. J.-H, Oh. K.J., Jeong. C.H., Yu. Y.G., Shin, Y.K. 2014. Beta-amyloid oligomers activate apoptotic BAK pore for cytochrome c release Biophys. J. 107(7):1601-1608. (featured in New and Notable by Daniel A. Linseman in Biophysical Journal, Oct. 2014, volume 107, pp1491-1492) [Biophysical Journal]
• Song, S.S., Lee, W.K., Aluvila, S., Oh, K.J., and Yu, Y.G. 2014. Identification of inhibitors against BAK pore formation using an improved in vitro system. Bull. Korean Chem. Soc. 35(2):419-424. [Korean Chem. Soc.]
• Aluvila, S., Mandal, T., Hustedt, E., Fajer, P., Choe, J.Y., and Oh, K.J. 2014. Organization of the mitochondrial apoptotic BAK pore: OLIGOMERIZATION OF THE BAK HOMODIMERS. J. Biol. Chem. 289:2537-2551 (Epub 2013 Dec 11). [medline] {Featured as one of the Key Scientific Articles in the Global Medical Discovery in April 2014) [Global Medical Discovery]
• Chen, D.Y., Lee, Y., Van Tine, B.A., Searleman, A.C., Westergard, T.D., Liu, H., Tu. H.C., Takeda, S., Dong, Y., Piwnica-Worms, D.R., Oh, K.J., Korsmeyer, S.J., Hermone, A., Gussio, R., Shoemaker, R.H., Cheng, E.H., and Hsieh, J.J. 2012.  A pharmacologic inhibitor of the protease Taspase1 effectively inhibits breast and brain tumor growth. Cancer Res. 72(3):736-746 (Epub 2011 Dec 13). [NIH]
• Oh, K.J., Singh, P., Lee, K., Foss, K., Lee, S., Park, M., Lee, S., Aluvila, S., Park, M., Singh, P., Kim, R.-S., Symersky, J. and Walters, D.E. 2010. Conformational Changes in BAK, a Pore-forming Proapoptotic Bcl-2 Family Member, upon Membrane Insertion and Direct Evidence for the Existence of BH3-BH3 Contact Interface in BAK Homo-oligomers J. Biol. Chem. 285: 28924-28937. [medline]
• Mayor, J.A., Sun, J., Kotaria, R., Walters, D. E., Oh, K.J., and Kaplan, R.S. 2010. Probing the Effect of Transport Inhibitors on the Conformation of the Mitochondrial Citrate Transport Protein via a Site-Directed Spin Labeling Approach. J. Bioenerg. Biomembr. 42: 99-109. [medline]
• Martinez-Caballero, S., Dejean, L.M., Kinnally, M.S., Oh, K.J., Mannella, C.A., Kinnally, K.W. 2009. Assembly of the mitochondrial apoptosis-induced channel, MAC. J. Biol. Chem. 284: 12235 - 12245. [medline] 
• Sun, Z-Y J., Oh, K.J., Kim, M., Yu, J., Brusic, V., Song, L., Qiao, Z., Wang, J-H., Wagner, G., Reinherz, E.L.  2008. HIV-1 broadly neutralizing antibody extracts its epitope from a kinked gp41 ectodomain region on the viral membrane. Immunity 28:52-63. [medline]
• Walensky, L.D., Pitter, K., Morash, J., Oh, K.J., Barbuto, S., Fisher, J., Smith, E., Verdine, G.L., Korsmeyer, S.J. 2006. A stapled BID BH3 helix directly binds and activates BAX. Molecular Cell 24:199-210. [medline]
• Oh, K.J., Barbuto, S., Pitter, K., Morash, J., Walensky, L.D., Korsmeyer, S.J. 2006. A membrane-targeted BID BH3 peptide is sufficient for high potency activation of BAX in vitro. J. Biol. Chem. 281: 36999-37008. [medline]
• Oh, K.J., Barbuto, S., Meyer, N., Korsmeyer, S.J. 2005. Conformational changes in BID, a pro-apoptotic BCL-2 family member, in membranes:  A site-directed spin labeling study.  J. Biol. Chem. 280: 753-767. [medline]
• Altenbach. C., Oh, K.J., Trabanino, R.J., Hideg, K., Hubbell, W.L. 2001. Estimation of inter-residue distances in spin labeled proteins at physiological temperatures: experimental strategies and practical limitations.  Biochemistry 25: 15471-15482. [medline]
• Zha, J., Weiler, S., Oh, K.J., Wei, M., and Korsmeyer, S. 2000. Post-translational myristoylation of BID facilitates its targeting to mitochondria and enhances its pro-apoptotic activity. Science 290: 1761-1765. [medline]
• Korsmeyer, S.J., Wei, M.C., Saito, M., Weiler, S., Oh, K.J., and Schlesinger, P.H. 2000.  Pro-apoptotic cascade activates BID, which oligomerizes BAK or BAX into pores that result in the release of cytochrome c. Cell Death Differ. 7(12): 1166-1173. [medline]
• Langen, R., Oh, K.J., Cascio, D., Hubbell, W.L. 2000. Crystal structures of spin labeled T4 lysozyme mutants: Implications for the interpretation of EPR spectra in terms of structure. Biochemistry 39: 8396-8405. [medline]
• Finkelstein, A., Oh, K.J., Senzel, L., Gordon, M., Blaustein, R.O., and Collier, R.J. 2000.  The diphtheria toxin channel-forming T-domain translocates its own NH2-terminal region and the catalytic domain across planar phospholipid bilayers. Int. J. Med. Microbiol. 290: 435-440. [medline]
• Senzel, L., Gordon, M., Blaustein, R.O., Oh, K.J., Collier, R.J., and Finkelstein, A. 2000. Topology of Diptheria toxin’s T-domain in the open channel state. J. Gen. Physiol. 115: 421-434. [medline]
• Oh, K.J., Altenbach, C., Collier, R.J., and Hubbell, W.L. 2000. Site-directed spin-labeling: Applications to Diptheria toxin. In: Methods in Molecular Biology: Bacterial Toxins Methods and Protocols. Ed. O Holst. Humana Press, vol. 145, pp. 147-169. [medline]
• Oh, K.J., Zhan, H., Cui, C., Altenbach, C., Hubbell, W.L., and Collier, R.J. 1999. Conformation of the Diphtheria toxin T-domain in membranes: A site-directed spin-labeling study of the TH8 helix and TL5 loop. Biochemistry 38: 10336-10343. [medline]
• Oh, K.J., Senzel, L., Collier, R.J., and Finkelstein, A. 1999. Translocation of the catalytic domain of Diphtheria toxin across planar phospholipid bilayers by its own T-domain. Proc. Natl. Acad. Sci.  USA. 96; 8467-8470. [medline]
• Huynh, P.D., Cui, C., Zhan, H., Oh, K.J., Collier, R.J., and Finkelstein, A. 1997.  Probing the structure of the Diphtheria toxin Channel.  Reactivity in planar lipid bilayer membranes of cysteine-substituted mutant channels with methanethiosulfonate derivatives. J. Gen. Physiol. 110: 229-242. [medline]
• Mchaourab, H.S., Oh, K.J.,  Fang, C.J., and Hubbell, W.L. 1997.  The conformation of T4 Lysozyme in solution.  Hinge bending motion and the substrate-induced conformational transition studied by site-directed spin labeling. Biochemistry 36: 307-316. [medline]
• Oh, K.J., Zhan, H., Cui, C., Hideg, K., Collier, R.J., and Hubbell, W.L. 1996. Organization of Diphtheria toxin T domain in bilayers: A site-directed spin labeling study. Science 273:810-812. [medline]
• Zhan, H., Oh, K.J., Shin, Y.-K., Hubbell, W.L., and Collier, R.J. 1995.  Interaction of the isolated transmembrane domain of Diphtheria toxin with membranes. Biochemistry 34: 4856-4863. [medline]
• Oh, K.J., Choi, S.J., and Yang, C.H. 1987.  Molecular cloning of hydrogenase gene in E. coli. Korean Biochem. J. 20(2): 129-136.