Director of Biomolecular Crystallography Center
Professor of Department of Chemistry/ School of Chemical Engineering and Bioengineering/ Molecular Plant Biology/ School of Biological Sciences/ School of Molecular Biosciences/ Washington Center for Muscle Biology
Pullman, WA 99164-4630
Research Fellow, 1988-1992
Massachusettes Institute of Technology, Cambridge, MA
Post-Doctoral Study, 1988-1989
Lawrence Berkeley National Laboratory, Berkeley, CA
Ph.D. Biophysics & Chemistry, 1987 University of California, Berkeley, CA
B.S. (1980), M.S. (1982) Physics & Microbiology, Seoul National University, Seoul, Korea
The major sarcoplasmic reticulum (SR) protein, calsequestrin (Casq), binds Ca2+ ions with high capacity (40-80 mol Ca2+), but moderate affinity (Kd =1mM) over the physiological Ca2+ concentration range and releases it with a high off-rate. Therefore, Casq has been proposed as a Ca2+ buffer inside the SR and/or an allosteric sensor of the fall in SR Ca2+ concentration. Cardiac Casq mutations cause of catecholaminergic polymorphic ventricular tachycardia (CPVT2), an arrhythmogenic disorder with a high mortality rate. Mutations to skeletal Casq have been also identified as causes or enablers of malignant hyperthermia (MH) and other skeletal muscle diseases, like vacuolar aggregate myopathy and central core disease. In addition, defective post-translational modifications of Casq, have been linked to cardiac pathology.We have been studying the unique mechanism by which Casq regulates SR Ca2+, and provided a basic insight into its calcium sequestration and the altered behavior of post-translationally modified and/or mutated Casq. We have discovered that many pharmaceutical drugs with muscle-related or cardiotoxic side effects, a common side effect seen in many synthetic pharmaceutical drugs, bind to and interfere with the normal functions of Casq.
Our study has provided fundamental mechanism of high capacity Ca sequestration and essential insight into how drugs with notorious muscle-related side effects can be improved and help design more effective treatments for CPVT.
Under the Energy Independence Security Act, the U.S. has established a national goal of replacing 30% of petroleum-based fuels with lignocellulosic fuels by the year 2030. Sorghum is an attractive feedstock that can be grown across much of the U.S. including low-productivity land. Sorghum can be harvested the same year it was planted, and thus offers the producers more flexibility. The most common process for converting biomass into biofuels is via fermentation of monomeric sugars obtained from cellulose and hemicellulosic polysaccharides in the plant cell walls. The efficiency of currently applied methods for the manufacturing of plant cellulose-based biofuels is significantly hindered by the presence of lignin in the cell wall. Lignin, an aromatic polymer formed from the oxidative coupling of hydroxycinnamyl alcohols and related compounds, shields cellulose from the hydrolytic enzymes. In addition, the enzymes adhere irreversibly to the lignin, rendering them inactive, and breakdown of lignin during pretreatment releases aromatic compounds that inhibit microbial fermentation. Hence, lignin poses a major challenge to large-scale and economically efficient biofuel production. Therefore, manipulating lignin content, subunit composition, and recalcitrance as a way to enhance biomass conversion is a major target, along with ways to boost cellulose content. Reports on plants with altered cell wall composition indicate that the yield of fermentable sugars can be increased, but that there can also be a penalty on biomass yield and/or plant fitness and survivability under field conditions, indicating the need for a sophisticated and tailored approach to control plant lignification. We approach this with the detailed structural and mechanistic knowledge of the key enzymes in the monolignol biosynthetic pathway, which will facilitate efficient and targeted manipulation of lignin subunit composition and lignin content, while maintaining plant viability. In addition, this detailed knowledge on monolignol biosynthetic enzymes can lead to the synthesis of novel phenolic compounds with antioxidant or plant-protective properties that can enhance the value of the crop. We have already shown successfully the promise of this approach by combining the structural analysis of the sorghum enzymes; caffeoyl-CoA O-methyltransferase (CCoAOMT), cinnamoyl-CoA reductase (CCR), peroxidase (PRX), cinnamyl alcohol dehydrogenase (CAD), caffeic acid O-methyltransferase (COMT) and hydroxycinnamoyltransferase (HCT) with enzymatic analysis.
Several polychlorophenols, such as 2,4,5-, 2,4,6-trichlorophenol (TCP), and pentachlorophenol (PCP) are primarily introduced into the environment through their use as preservatives in the wood industry, as herbicides in agriculture, and as general biocides in consumer products. They persist in the environment because halogen substitution makes them recalcitrant to degradation.
Our research focuses on critical monooxygenases and dioxygenates. We have successfully determined the 3D-structure of many participating enzymes allowing us to investigate and compare the unique activities and substrate specificities of the enzymes using site-directed mutagenesis as well as kinetic and thermodynamic characterizations of the enzyme, cofactor and substate interactions. Determination of the 3-D structures will provide insight about their substrate specificity eventually allowing us to rationally design the active sites of enzymes to obtain desired specificities. The systematic structural and biophysical approaches and the designed mutants will offer information not only for the interaction between its unique substrate and active site amino acid residues but the reaction mechanisms.
Intensive efforts are taking place to determine the structures of various cancer-associated proteins and types of damaged DNA, including oxidative and UV damaged, and, ultimately, to develop anticancer drugs. Using complex crystal structures and binding studies, the search for new anti-cancer drugs that are free of side effects, are being carried out. We are also investigating key plant enzymes involved in various pathways, which have important and direct connections with human health such as chemoprotection against various cancers, lowering blood cholesterol levels, and as antifungal/antiviral agents, biocides, antifeedants, and antioxidants. These studies will be used to develop treatments for various cancers.
- Lewis KM, Munske GR, Byrd SS, Kang J,Cho HJ, Rios E and Kang C (2016) Characterization of Post-Translational Modifications to Calsequestrins of Cardiac and Skeletal Muscle. Int. J. Mol. Sci. 17, 1539.
- Walker AM, Sattler SA, Regner M, Jones JP, Ralph J, Vermerris W, Sattler SE and Kang C (2016). Determination of the structure and catalytic mechanism of Sorghum bicolor caffeoyl-CoA O-methyltransferase. Plant Physiology 172, 78-92.
- Springer A, Kang C, Rustgic S, Wettstein D, Reinbothe C, Pollmann S, and Reinbothe S. (2016) Programmed chloroplast destruction during leaf senescence Q:4; 5 involves 13-lipoxygenase (13-LOX). PNAS 113, 3383-3388.
- Jun S-Y, Lewis KM, Youn B, Xun L and Kang C (2016). Structural and Biochemical Characterization of EDTA Monooxygenase and its Physical Interaction with a Partner Flavin Reductase. Mol Microbiol 100, 989-1003.
- Lewis KM, Ronish LA, Ríos E and Kang C. (2015) Characterization of Two Human Skeletal Calsequestrin Mutants Implicated in Malignant Hyperthermia and Vacuolar Aggregate Myopathy. JBC 290, 28665-28674.