中央研究院 生物化學研究所

研究領域與專長

實驗室的研究著重於蛋白的結構、功能與生物物理性質的瞭解。所探討的成果 可以應用在癌症治療的抑制劑設計或工業酵素的設計。本實驗室之研究常用到蛋白晶體學、光譜學及酵素學等相關技術，並且經常性與其他實驗室進行合作。你可在http://ho.ibc.sinica.edu.tw/ 找到更多本實驗室的相關資訊。

目前實驗室主要研究方向有三：(1) 稻米抗淹水蛋白的調控機制 (2)與癌症有關的蛋白間交互作用 (3)工業用酵素的設計。

1. 稻米抗淹水蛋白的調控機制：
   • 根據人口成長預測，在下個二十年內農業產量必須成長兩倍才能確保國際食物安全。多數的糧食作物包含水耕的稻米種都無法在淹水滅頂情形下生存。然而近年的氣候變遷導致的極端天氣例如:洪水，使得兩倍的糧食產量目標越來越難以達到。部分野生稻米種具有一關鍵的轉錄因子Sub1A-1使其能在長達兩週的滅頂情況下，依然能夠生存。先前研究已經顯示Sub1A-1能夠啟動發酵代謝(低氧環境下的能量產生方式)、保存碳水化合物(為了水退之後的重新生長)、抑制生長及延遲開花。在水消退後，植物的回復機制往往會導致快速脫水，使得植物開始落葉最終死亡。令人驚奇的是，Sub1A-1也同時會轉錄活化一些與乾旱有關的蛋白來保護蛋白免於前述的結果。雖然，目前知道Sub1A-1能有效保護稻米抵抗淹水並得以存活，但其分子機制以與下游訊號傳遞機制仍未被了解 在本研究中，我們將計劃藉由生物化學與生物物理方式並整合我們現有的微陣列資料來研究Sub1A-1的DNA結合專一性以揭露其下游調控機制。 全球三分之一的稻米產區，為易淹水的區域，我們希望此研究發現可以提供一個保護稻米的方法得以穩定稻米的產量。
2. 與癌症有關的蛋白間交互作用：
   • 經由動物和人類癌細胞實驗中證實酪氨酸蛋白磷酸酶（Protein tyrosine phosphatases PTPs） 人類的癌症致發是高度相關。在PTPs家族中的receptor-like PTPα (rPTPα) 可以藉由去磷酸化進一步活化原致癌因子的Src。在整個訊息傳遞過程中，rPTPα蛋白受到生長因子結合蛋白Grb2蛋白的調控，使得Src蛋白的致癌訊息傳遞機制得以抑制。故此專案在結合結構生物學與分子生物學的專長以解決有關癌症的細胞訊息傳遞問題。此專案的蛋白複合體結構研究分為三個階段:第一階段，證明rPTPα能調控生長因子結合蛋白Grb2蛋白的磷酸化狀態。第二階段，了解rPTPα與生長因子結合蛋白Grb2與Src之間相互間的調節關聯。第三階段，取得a) rPTPα與生長因子結合蛋白Grb2和 b)rPTPα與原致癌因子Src之蛋白複合體結構資訊。
   • 蛋白質甲基化是一種常見的蛋白質後修飾(post-translational modification)與訊息傳遞(signal transduction)、基因轉錄(gene transcription)、mRNA剪接(mRNA splicing)等重要的功能有關。而甲基化轉移?的表現量異常是癌症生成中一個重要特徵。 精氨酸甲基轉移脢(Protein Arginine Methyltransferases, PRMTs)藉由甲基化許多癌症相關蛋白而在癌症生成扮演重要角色。然而哪一特定的蛋白被甲基化進而使得細胞癌化則是未知。因此我們藉由闡明PRMT與蛋白形成複合體之結構來提供結構概念以解答此問題。此外，我們的發現促進防止甲基化抑制劑的設計，藉此找尋新的癌症治療藥劑。
   • KLHL20是一種連接蛋白(protein adapator)，其與癌症抑制蛋白PML (tumor suppressor) 行交互作用而導致PML降解，因此導致腫瘤增生。抑制KLHL20-PML之間交互作用之抑制劑對新癌症療法的開發十分有幫助。目前我們正在進行KLHL20-PML複合體結構之解析，以將所得之資料用於抑制劑的設計。
3. 工業用酵素設計：
   • 許多催化特殊反應之酵素在工業上都有用處。對酵素生化/生物物理的改造能擴大酵素於工業上的應用範圍。基於結構上的分析了解，我們目前致力於強化纖維素酶的化學性質(受質多樣化)以應用於生物燃料方面，同時也對我們已申請專利的角蛋白酶進行物理性質之強化(耐高溫與耐強酸鹼值)來應用於畜牧用的飼料添加劑。

學經歷

• 2001 – 2007   博士, 生理暨生物物理系, 波士頓大學
• 1995 – 1999   學士, 化學系, 清華大學

• 2019 – 迄今   副研究員, 中研院生化所
• 2011 – 2019   助研究員, 中研院生化所
• 2007 – 2011   博士後研究員, 美國 阿爾伯特•愛因斯坦 醫學院生化系

主要著作

Diamidine compounds for selective inhibition of protein arginine methyltransferase 1. 
Yan L, Yan C, Qian K, Su H, Kofsky-Wofford SA, Lee WC, Zhao X, Ho MC, Ivanov I, Zheng YG 
Journal of medicinal chemistry (2014)

Catalytic Site Conformations in Human PNP by (19)F-NMR and Crystallography. 
Suarez J, Haapalainen AM, Cahill SM, Ho MC, Yan F, Almo SC, Schramm VL 
Chemistry & biology (2013)

Structure of the Arginine Methyltransferase PRMT5-MEP50 Reveals a Mechanism for Substrate Specificity. 
Meng-Chiao Ho, Carola Wilczek, Jeffrey B. Bonanno, Li Xing, Janina Seznec, Tsutomu Matsui, Lester G. Carter, Takashi Onikubo, P. Rajesh Kumar, Man K. Chan, Michael Brenowitz, R. Holland Cheng, Ulf Reimer, Steven C. Almo, David Shechter 
PLoS ONE (2013)

Characterizing DNA methyltransferases with an ultrasensitive luciferase-linked continuous assay. 
Hemeon I, Gutierrez J.A., Ho MC., Schramm V.L. 
Anal Chem. (2011)

Entropy-driven binding of picomolar transition state analogue inhibitors to human 5’-methylthioadenosine phosphorylase. 
Guan R, Ho MC, Brenowitz M, Tyler PC, Evans GB, Almo SC, Schramm VL 
Biochemistry (2011)

Methylthioinosine phosphorylase from Pseudomonas aeruginosa. Structure and annotation of a novel enzyme in quorum sensing. 
Guan R, Ho MC, Almo SC, Schramm VL 
Biochemistry (2011)

Four generations of transition-state analogues for human purine nucleoside phosphorylase. 
Ho MC, Shi W, Rinaldo-Matthis A, Tyler PC, Evans GB, Clinch K, Almo SC, Schramm VL 
Proceedings of the National Academy of Sciences of the United States of America (2010)

A phosphoenzyme mimic, overlapping catalytic sites and reaction coordinate motion for human NAMPT. 
Burgos ES, Ho MC, Almo SC, Schramm VL 
Proceedings of the National Academy of Sciences of the United States of America (2009)

The origin of the electrostatic perturbation in acetoacetate decarboxylase. 
Ho MC, Menetret JF, Tsuruta H, Allen KN 
Nature (2009)

Transition state analogues in structures of ricin and saporin ribosome-inactivating proteins. 
Ho MC, Sturm MB, Almo SC, Schramm VL 
Proceedings of the National Academy of Sciences of the United States of America (2009)

著作列表

1. Hsieh JY, Chen KC, Wang CH, Liu GY, Ye JA, Chou YT, Lin YC, Lyu CJ, Chang RY, Liu YL, Li YH, Lee MR, (Ho MC)*, Hung HC*  (2023-05)  Communications Biology  6(1), 548  "Suppression of the human malic enzyme 2 modifies energy metabolism and inhibits cellular respiration."
   
2. Chen NC, Wang CH, Yoshimura M, Yeh YQ, Guan HH, Chuankhayan P, Lin CC, Lin PJ, Huang YC, Wakatsuki S, (Ho MC)*, Chen C*  (2023-02)  Nature communications  14(1), 545  "Structures of honeybee-infecting Lake Sinai virus reveal domain functions and capsid assembly with dynamic motions."
   
3. Lai L, Cheung YW, Martinez M, Kixmoeller K, Palao L 3rd, Steimle S, (Ho MC), Black BE, Lai EM, Chang YW  (2023)  Methods in molecular biology  2646, 211-248  "In Situ Structure Determination of Bacterial Surface Nanomachines Using Cryo-Electron Tomography."
   
4. Tsai MD*, Wu WJ, (Ho MC)  (2022-05)  Annual review of biophysics  51, 19-38  "Enzymology and Dynamics by Cryogenic Electron Microscopy."
   
5. Shih O, Liao KF, Yeh YQ, Su CJ, Wang CA, Chang JW, Wu WR, Liang CC, Lin CY, Lee TH, Chang CH, Chiang LC, Chang CF, Liu DG, Lee MH, Liu CY, Hsu TW, Mansel B, (Ho MC), Shu CY, Lee F, Yen E, Lin TC, Jeng U*  (2022-04)  JOURNAL OF APPLIED CRYSTALLOGRAPHY  55(2), 340-352  "Performance of the new biological small- and wide-angle X-ray scattering beamline 13A at the Taiwan Photon Source"
   
6. Fulton MD, Cao M, (Ho MC), Zhao X, Zheng YG  (2021-10)  Journal of biological chemistry  297(4), 101123  "The Macromolecular Complexes of Histones Affect Protein Arginine Methyltransferase Activities."
   
7. Hsieh JY, Yang HP, Tewary SK, Cheng HC, Liu YL, Tai SC, Chen WL, Hsu CH, Huang TJ, Chou CJ, Huang YN, Peng CT, (Ho MC)*, Liu GY*, Hung HC*  (2021-02)  iScience  24(2), 102034  "Single nucleotide variants lead to dysregulation of the human mitochondrial NAD(P)+-dependent malic enzyme."
   
8. 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*  (2021-01)  Nature Communications  12(1), 115  "Identification of fidelity-governing factors in human recombinases DMC1 and RAD51 from cryo-EM structures."
   
9. Qian K, Yan CL, Su HR, Dang T, Zhou B, Wang ZY, Zhao XY, Ivanov I, (Ho MC), Zheng YG*  (2021-01)  RSC Medicinal Chemistry  12(1), 95-102  "Pharmacophore-based screening of diamidine small molecule inhibitors for protein arginine methyltransferases."
   
10. Liu YM, Mahmud Md. SA, Chen XR, Chen TH, Liao KS, Lo JM, Wu YM, (Ho MC), Wu CY, Wong CH, Jan JT, Ma C  (2020-08)  Cell Reports  32(6), 108016  "A carbohydrate-binding protein from the edible Lablab beans effectively blocks the infections of influenza viruses and SARS-CoV-2."
    
11. Anandharaj M, Lin YJ, Rani RP, Nadendla EK, (Ho MC), Huang CC, Cheng JF, Chang JJ, Li WH  (2020-02)  Proceedings of the National Academy of Sciences of the United States of America  117(5), 2385-2394  "Constructing a yeast to express the largest cellulosome complex on the cell surface."
    
12. Tewary SK, Zheng YG, (Ho MC*)  (2019-08)  Cellular and Molecular Life Sciences  76(15), 2917-2932  "Protein arginine methyltransferases: insights into the enzyme structure and mechanism at the atomic level."
    
13. 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  (2019-02)  Proceedings of the National Academy of Sciences of the United States of America  116(8), 3300-3309  "Regulatory cascade involving transcriptional and N-end rule pathways in rice under submergence."
    
14. Liang PH, Lin WL, Hsieh HY, Lin TY, Chen CH, Tewary SK, Lee HL, Yuan SF, Yang B, Yao JY, (Ho MC)  (2018-03)  Biochimica et Biophysica Acta - General Subjects  1862(3), 513-521  "A flexible loop for mannan recognition and activity enhancement in a bifunctional glycoside hydrolase family 5."
    
15. Fulton MD, Zhang J, He M, (Ho MC), Zheng YG  (2017-07)  Biochemistry  56(28), 3539-3548  "Intricate Effects of alpha-Amino and Lysine Modifications on Arginine Methylation of the N-Terminal Tail of Histone H4."
    
16. Wu WL, Chen MY, Tu IF, Lin YC, EswarKumar N, Chen MY, (Ho MC*), Wu SH  (2017-07)  Scientific reports  7(1), 4658  "The discovery of novel heat-stable keratinases from Meiothermus taiwanensis WR-220 and other extremophiles."
    
17. Hu H, Qian K, (Ho MC), Zheng YG  (2016-03)  Expert opinion on investigational drugs  25(3), 335-358  "Small Molecule Inhibitors of Protein Arginine Methyltransferases."
    
18. Liu MS, Tsai HY, Liu XX, (Ho MC), Wu WJ*, Tsai MD*  (2016-02)  Journal of the American Chemical Society  138(7), 2389-2398  "Structural Mechanism for the Fidelity Modulation of DNA Polymerase λ"
    
19. Lee WC, Lin WL, Matsui T, Chen ES, Wei TW, Lin WH, Hu H, Zheng YG, Tsai MD, (Ho MC)  (2015-12)  Biochemistry  54(51), 7514-7523  "PROTEIN ARGININE METHYLTRANSFERASE 8: tetrameric structure and protein substrate specificity."
    
20. Yuan SF, Wu TH, Lee HL, Hsieh HY, Lin WL, Yang B, Chang CK, Li Q, Gao J, Huang CH, (Ho MC)*, Guo RT, Liang PH  (2015-02)  The Journal of biological chemistry  290(9), 5739-5748  "Biochemical Characterization and Structural Analysis of a Bifunctional Cellulase/Xylanase from Clostridium thermocellum."
    
21. Yan L, Yan C, Qian K, Su H, Kofsky-Wofford SA, Lee WC, Zhao X, (Ho MC), Ivanov I, Zheng YG  (2014)  Journal of medicinal chemistry  57(6), 2611-2622  "Diamidine compounds for selective inhibition of protein arginine methyltransferase 1."
    
22. Donaldson TM, Cassera MB, (Ho MC), Zhan C, Merino EF, Evans GB, Tyler PC, Almo SC, Schramm VL, Kim K  (2014)  Eukaryotic cell  13(5), 572-579  "INHIBITION AND STRUCTURE OF TOXOPLASMA GONDII PURINE NUCLEOSIDE PHOSPHORYLASE."
    
23. (Meng-Chiao Ho)*, Carola Wilczek, Jeffrey B. Bonanno, Li Xing, Janina Seznec, Tsutomu Matsui, Lester G. Carter, Takashi Onikubo, P. Rajesh Kumar, Man K. Chan, Michael Brenowitz, R. Holland Cheng, Ulf Reimer, Steven C. Almo, David Shechter*  (2013-02)  PLoS ONE  8(2), e57008  "Structure of the Arginine Methyltransferase PRMT5-MEP50 Reveals a Mechanism for Substrate Specificity."
    
24. Suarez J, Haapalainen AM, Cahill SM, (Ho MC), Yan F, Almo SC, Schramm VL  (2013)  Chemistry & biology  20(2), 212-222  "Catalytic Site Conformations in Human PNP by (19)F-NMR and Crystallography."
    
25. Guan R, (Ho MC), Frohlich RF, Tyler PC, Almo SC, Schramm VL*  (2012-11)  Biochemistry  51(45), 9094-9103  "Methylthioadenosine Deaminase in an Alternative Quorum Sensing Pathway in Pseudomonas aeruginosa."
    
26. Ke S, (Ho MC), Zhadin N, Deng H, Callender R.*  (2012-05)  J Phys Chem B  116(21), 6166-6176  "Investigation of catalytic loop structure, dynamics, and function relationship of Yersinia protein tyrosine phosphatase by temperature-jump relaxation spectroscopy and X-ray structural determination."
    
27. Cassera MB, (Ho MC), Merino EF, Burgos ES, Rinaldo-Matthis A, Almo SC, Schramm VL  (2011)  Biochemistry  50(11), 1885-1893  "A high-affinity adenosine kinase from Anopheles gambiae."
    
28. Hemeon I, Gutierrez J.A., (Ho MC.), Schramm V.L.  (2011)  Anal Chem.  83(12), 4996-5004  "Characterizing DNA methyltransferases with an ultrasensitive luciferase-linked continuous assay."
    
29. Guan R, (Ho MC), Brenowitz M, Tyler PC, Evans GB, Almo SC, Schramm VL  (2011)  Biochemistry  50(47), 10408-10417  "Entropy-driven binding of picomolar transition state analogue inhibitors to human 5'-methylthioadenosine phosphorylase."
    
30. Guan R, (Ho MC), Almo SC, Schramm VL  (2011)  Biochemistry  50(7), 1247-1254  "Methylthioinosine phosphorylase from Pseudomonas aeruginosa. Structure and annotation of a novel enzyme in quorum sensing."
    
31. Cassera MB, Hazleton KZ, Merino EF, Obaldia N 3rd, (Ho MC), Murkin AS, Depinto R, Gutierrez JA, Almo SC, Evans GB, Babu YS, Schramm VL  (2011)  PloS one  6(11), e26916  "Plasmodium falciparum Parasites Are Killed by a Transition State Analogue of Purine Nucleoside Phosphorylase in a Primate Animal Model."
    
32. (Ho MC), Shi W, Rinaldo-Matthis A, Tyler PC, Evans GB, Clinch K, Almo SC, Schramm VL  (2010)  Proceedings of the National Academy of Sciences of the United States of America  107(11), 4805-4812  "Four generations of transition-state analogues for human purine nucleoside phosphorylase."
    
33. Burgos ES, (Ho MC), Almo SC, Schramm VL  (2009)  Proceedings of the National Academy of Sciences of the United States of America  106(33), 13748-13753  "A phosphoenzyme mimic, overlapping catalytic sites and reaction coordinate motion for human NAMPT."
    
34. (Ho MC), Cassera MB, Madrid DC, Ting LM, Tyler PC, Kim K, Almo SC, Schramm VL  (2009)  Biochemistry  48(40), 9618-9626  "Structural and metabolic specificity of methylthiocoformycin for malarial adenosine deaminases."
    
35. (Ho MC), Menetret JF, Tsuruta H, Allen KN  (2009)  Nature  459(7245), 393-397  "The origin of the electrostatic perturbation in acetoacetate decarboxylase."
    
36. Gutierrez JA, Crowder T, Rinaldo-Matthis A, (Ho MC), Almo SC, Schramm VL  (2009)  Nature chemical biology  5(4), 251-257  "Transition state analogs of 5'-methylthioadenosine nucleosidase disrupt quorum sensing."
    
37. (Ho MC), Sturm MB, Almo SC, Schramm VL  (2009)  Proceedings of the National Academy of Sciences of the United States of America  106(48), 20276-20281  "Transition state analogues in structures of ricin and saporin ribosome-inactivating proteins."
    
38. Chi Y, Kumar TK, Wang HM, (Ho MC), Chiu IM, Yu C  (2001)  Biochemistry  40(25), 7746-7753  "Thermodynamic characterization of the human acidic fibroblast growth factor: evidence for cold denaturation."