Institute of Biological Chemistry, Academia Sinica

Research

Our research interests are mainly focused on the structure, function, and biophysical properties of proteins. The information we discovered can further guide the inhibitor design to aid in cancer therapy or enzyme engineering for industrial uses. We conduct our studies primarily using X-ray crystallography, spectroscopy and enzymology and routinely collaborates with other laboratories worldwide.

Our current studies involves three areas: (1) reconstruct the rice survival strategy under submergence (2) protein-protein interaction related to cancer (3) enzyme engineering for industrial use.

1. Reconstruct the rice survival strategy under submergence:
   • Most rice cultivars die within a week of complete submergence, but some rice cultivars show high tolerance and survive up to two weeks under complete submergence. It’s believed that Sub1A is the key transcription factor that regulates quiescence responses enabling prolonged submergence. We aim to understand Sub1A1 regulatory networks. We will study the DNA binding specificity of Sub1A-1 to reveal the downstream signaling pathway via biochemical and biophysical approaches combined with our microarray data and the functions of other domains by structural approaches.
2. Protein-protein interaction related to cancer:
   • The receptor-like protein tyrosine phosphatase-α (rPTPα) is a crucial player in mediating RTK/Src signal transduction pathways. Because rPTPα can activate Src and is overexpressed in various cancers, rPTPα is considered as proto-oncogene. The rPTPα can be phosphorylated by RTK to become the active form, and is also subject to oxidation by ROS. However, detailed information at the molecular level is missing largely due to lack of structures of true protein-phosphoprotein complexes. The major challenges in such structural studies include 1) to produce a large quantity of protein-phosphoprotein complexes involving specifically modified rPTPα; 2) to crystallize the protein complexes. We would like to address a) how rPTPα activates the activity of Src b) how oxidation of rPTPα affects its activity to activate Src.
   • Protein arginine methyltransferases (PRMTs) play roles in cancer progression by methylating many cancer related proteins. However, the question remains which protein methylation leads to oncogenic activation. Our structural approaches focusing on PRMT-protein complex provide a way to answer this question and can assist inhibitor design to prevent methylation for cancer therapy.
   • KLHL20, a protein adaptor, interacts with the tumor suppressor, PML. This interaction induces the degradation of PML which leads to tumor progression. Inhibitors that prevent KLHL20-PML interaction may be useful in cancer therapy. We are now working on the KLHL20-PML complex structure which can provide a blueprint for inhibitor design.
3. Enzyme engineering for industrial use:
   • Many enzymes that catalyze specific reactions have industrial applications. The biochemical/biophysical modifications of enzymes by protein engineering can broaden the uses in the industry. Based on structural analyses, we aim to improve chemical properties of cellulase (substrate variety) for biofuel application and physical properties (heat and pH tolerance) of our patented keratinase for animal feed application.

Degrees and Positions Held

• 2001 – 2007   Ph.D., Physiology & Biophysics, Boston University
• 1995 – 1999   B.S., Chemistry, National Tsing-Hua University

• 2019 – present   Associate Research Fellow, Institute of Biological Chemistry, Academia Sinica
• 2011 – 2019   Assistant Research Fellow, Institute of Biological Chemistry, Academia Sinica
• 2007 – 2011   postdoctoral researcher, Albert Einstein College of Medicine of Yeshiva University

Selected Publications

Structural basis for calcium-stimulating pore formation of Vibrio α-hemolysin. 
Chiu YC, Yeh MC, Wang CH, Chen YA, Chang H, Lin HY, Ho MC, Lin SM 
Nature Communications (2023)

Visualizing the membrane disruption action of antimicrobial peptides by cryo-electron tomography. 
Chen EH, Wang CH, Liao YT, Chan FY, Kanaoka Y, Uchihashi T, Kato K, Lai L, Chang YW, Ho MC*, Chen RP* 
Nature Communications (2023)

A RAD51-ADP double filament structure unveils the mechanism of filament dynamics in homologous recombination. 
Luo SC, Yeh MC, Lien YH, Yeh HY, Siao HL, Tu IP, Chi P, Ho MC* 
Nature Communications (2023)

SUB1A-1 anchors a regulatory cascade for epigenetic and transcriptional controls of submergence tolerance in rice. 
Lin CC, Lee WJ, Zheng CY, Chou MY, Lin TJ, Lin CS, Ho MC*, Shih MC* 
PNAS Nexus (2023)

Structures of honeybee-infecting Lake Sinai virus reveal domain functions and capsid assembly with dynamic motions. 
Chen NC, Wang CH, Yoshimura M, Yeh YQ, Guan HH, Chuankhayan P, Lin CC, Lin PJ, Huang YC, Wakatsuki S, Ho MC*, Chen CJ* 
Nature Communications (2023)

Identification of fidelity-governing factors in human recombinases DMC1 and RAD51 from cryo-EM structures. 
Luo SC, Yeh HY, Lan WH, Wu YM, Yang CH, Chang HY, Su GC, Lee CY, Wu WJ, Li HW, Ho MC*, Chi P*, Tsai MD* 
Nature Communications (2021)

Protein arginine methyltransferases: insights into the enzyme structure and mechanism at the atomic level. 
Tewary SK, Zheng YG, Ho MC* 
Cellular and Molecular Life Sciences (2019)

Regulatory cascade involving transcriptional and N-end rule pathways in rice under submergence. 
Lin CC, Chao YT, Chen WC, Ho HY, Chou MY, Li YR, Wu YL, Yang HA, Hsieh H, Lin CS, Wu FH, Chou SJ, Jen HC, Huang YH, Irene D, Wu WJ, Wu JL, Gibbs DJ, Ho MC*, Shih MC* 
Proceedings of the National Academy of Sciences of the United States of America (2019)

Protein Arginine Methyltransferase 8: Tetrameric Structure and Protein Substrate Specificity. (cover article) 
Lee WC, Lin WL, Matsui T, Chen ES, Wei TY, Lin WH, Hu H, Zheng YG, Tsai MD, Ho MC* 
Biochemistry (2015)

Structure of the Arginine Methyltransferase PRMT5-MEP50 Reveals a Mechanism for Substrate Specificity. 
Ho MC*, Wilczek C, Bonanno JB, Xing L, Seznec J, Matsui T, Carter LG, Onikubo T, Kumar PR, Chan MK, Brenowitz M, Cheng RH, Reimer U, Almo SC, Shechter D* 
PLoS ONE (2013)

Publication List