專任研究人員
kpwu@gate.sinica.edu.tw +886-2-27855696,5070
吳昆峯 助研究員
研究領域與專長
學經歷
主要著作
著作列表

研究領域與專長

蛋白質泛素化、蛋白質類澱粉化與相關疾病藥物開發

我們的研究主題有二：
(1)蛋白質泛素化之機制探究，及相關連人類疾病之抗病藥物開發
後轉譯修飾在生物體內扮演了相當重要的功能調控角色。 舉凡磷酸修飾、甲基修飾、醣修飾等都是使用小分子直接在蛋白質的特定位置進行修飾。 然而泛素(ubiquitin)標記反應直接採用一個76顆氨基酸的小蛋白質(泛素)修飾在特定蛋白質上面。近半人體內的蛋白質都會被泛素修飾，絕大部分的泛素修飾產物會被帶往細胞內的蛋白酶體處理，如同細胞內的碎紙機把蛋白質絞碎後，回收氨基酸再利用。
我們近年專注於闡明泛素化跟病菌感染之免疫反應，新冠肺炎、登革熱、日本腦炎、感冒、肺結核等感染皆會改變細胞內的泛素化平衡，壓抑免疫力。藉由生物物理學、結構生物學、生物化學及合成生物學的技術，我們致力於闡明感染與泛素化機制，開發抗病菌藥物，提升本身的免疫反應。

(2)蛋白質類澱粉化與神經退化疾病的影響
諸多神經退化疾病都與蛋白質的類澱粉堆疊有關。其中帕金森氏症是僅次於阿茲海默症的神經退化疾病。導致神經退化而得到帕金森氏症的原因眾多，最常見的是腦細胞內的蛋白質 alpha-synuclein的長年性類澱粉化堆疊造成病變。導致alpha-synuclein類澱粉化堆疊的原因包含家族性遺傳、飲食來源、環境因子等，我們專注於探討此蛋白質從無序態逐步轉換成類澱粉化堆疊的過程，藉此找出關鍵的轉換機制，也致力於開發調控轉類澱粉化堆疊方法或藥物。

學經歷

  • 2004 – 2010   博士, 化學系, 美國新澤西州立羅格斯大學
  • 2000 – 2002   碩士, 生命科學研究所, 國立清華大學
  • 1996 – 2000   學士, 生命科學系, 國立清華大學
  • 2018 – 迄今   助研究員, 中央研究院生物化學研究所
  • 2017 – 2018   助理研究學者, 科技部
  • 2012 – 2017   博士後研究學者, 美國聖猶大兒童研究醫院結構生物部門
  • 2010 – 2012   博士後研究學者, 美國新澤西州立羅格斯大學先進生物科技與醫藥中心

主要著作

2.2 Å Cryo-EM Tetra-Protofilament Structure of the Hamster Prion 108-144 Fibril Reveals an Ordered Water Channel in the Center. 
Chen EH, Kao HW, Lee CH, Huang JYC, Wu KP*, Chen RP* 
Journal of the American Chemical Society (2022)

Structural basis for the helical filament formation of Escherichia coli glutamine synthetase. 
Huang PC, Chen SK, Chiang WH, Ho MR, Wu KP* 
Protein Science (2022)

A cascading activity-based probe sequentially targets E1-E2-E3 ubiquitin enzymes.  
Mulder MP, Witting K, Berlin I, Pruneda JN, Wu KP, Chang JG, Merkx R, Bialas J, Groettrup M, Vertegaal AC, Schulman BA, Komander D, Neefjes J, El Oualid F, Ovaa H  
Nature Chemical Biology (2016)

Dual RING E3 Architectures Regulate Multiubiquitination and Ubiquitin Chain Elongation by APC/C.  
Brown NG, VanderLinden R, Watson ER, Weissmann F, Ordureau A, Wu KP, Zhang W, Yu S, Mercredi PY, Harrison JS, Davidson IF, Qiao R, Lu Y, Dube P, Brunner MR, Grace CRR, Miller DJ, Haselbach D, Jarvis MA, Yamaguchi M, Yanishevski D, Petzold G, Sidhu SS, Kuhlman B, Kirschner MW, Harper JW, Peters JM, Stark H, Schulman BA  
Cell (2016)

System-Wide Modulation of HECT E3 Ligases with Selective Ubiquitin Variant Probes.  
Zhang W, Wu KP, Sartori MA, Kamadurai HB, Ordureau A, Jiang C, Mercredi PY, Murchie R, Hu J, Persaud A, Mukherjee M, Li N, Doye A, Walker JR, Sheng Y, Hao Z, Li Y, Brown KR, Lemichez E, Chen J, Tong Y, Harper JW, Moffat J, Rotin D, Schulman BA, Sidhu SS  
Molecular Cell (2016)

Fast hydrogen exchange affects ¹⁵N relaxation measurements in intrinsically disordered proteins.  
Kim S, Wu KP, Baum J  
Journal of Biomolecular NMR (2013)

Detection of transient interchain interactions in the intrinsically disordered protein alpha-synuclein by NMR paramagnetic relaxation enhancement.  
Wu KP, Baum J  
Journal of American Chemistry Society (2010)

Structural reorganization of alpha-synuclein at low pH observed by NMR and REMD simulations.  
Wu KP, Weinstock DS, Narayanan C, Levy RM, Baum J  
Journal of Molecular Biology (2009)

著作列表

  1. Ho MR, Wu YM, Lu YC, Ko TP, (Wu KP)*  (2023-06)  Journal of Structural Biology  215(2), 107958  "Cryo-EM reveals the structure and dynamics of a 723-residue malate synthase G"
  2. Chen YH, Chen HH, Wang WJ, Chen HY, Huang WS, Kao CH, Lee SR, Yeat NY, Yan RL, Chan SJ, (Wu KP), Chen RH*  (2023-05)  Nature Communications  14(1), 3050  "TRABID inhibition activates cGAS/STING-mediated anti-tumor immunity through mitosis and autophagy dysregulation."
  3. Chen EH, Kao HW, Lee CH, Huang JYC, (Wu KP)*, Chen RP*  (2022-08)  Journal of the American Chemical Society  144, 13888-13894  "2.2 Å Cryo-EM Tetra-Protofilament Structure of the Hamster Prion 108-144 Fibril Reveals an Ordered Water Channel in the Center."
  4. Yang TJ, Li TN, Huang RS, Pan MY, Lin SY, Lin S, (Wu KP), Wang LH, Hsu STD*  (2022-06)  JOURNAL OF CELL BIOLOGY  221(6), e202201094  "Tumor suppressor BAP1 nuclear import is governed by transportin-1."
  5. Huang PC, Chen SK, Chiang WH, Ho MR, (Wu KP)*  (2022-05)  Protein Science  31(5), e4304  "Structural basis for the helical filament formation of Escherichia coli glutamine synthetase."
  6. Weston KP, Gao X, Zhao J, Kim KS, Maloney SE, Gotoff J, Parikh S, Leu YC, (Wu KP), Shinawi M, Steimel JP, Harrison JS, Yi JJ.  (2021-11)  Nature Communications  12(1), 6809  "Identification of disease-linked hyperactivating mutations in UBE3A through large-scale functional variant analysis"
  7. Lo HS, Hui KPY, Lai HM, He X, Khan KS, Kaur S, Huang J, Li Z, Chan AKN, Cheung HH, Ng KC, Ho JCW, Chen YW, Ma B, Cheung PM, Shin D, Wang K, Lee MH, Selisko B, Eydoux C, Guillemot JC, Canard B, (Wu KP), Liang PH, Dikic I, Zuo Z, Chan FKL, Hui DSC, Mok VCT, Wong KB, Mok CKP, Ko H, Aik WS, Chan MCW, Ng WL  (2021-05)  ACS central science  7(5), 792-802  "Simeprevir Potently Suppresses SARS-CoV-2 Replication and Synergizes with Remdesivir."
  8. Chiu YH, Ko KT, Yang TJ, (Wu KP), Ho MR, Draczkowski P*, Hsu STD*  (2021-04)  Biochemistry  60(4), 1075-1079  "Direct Visualization of a 26 kDa Protein by Cryo-Electron Microscopy Aided by a Small Scaffold Protein."
  9. Chen YH, Huang TY, Lin YT, Lin SY, Li WH, Hsiao HJ, Yan RL, Tang HW, Shen ZQ, Chen GC, (Wu KP), Tsai TF, Chen RH*  (2021-02)  Nature Communications  12, 1322  "VPS34 K29/K48 branched ubiquitination governed by UBE3C and TRABID regulates autophagy, proteostasis and liver metabolism."
  10. Wang YS*, (Wu KP)*, Jiang HK, Kurkute P, Chen RH*  (2020-11)  Molecules  25(21), 5200  "Branched Ubiquitination: Detection Methods, Biological Functions and Chemical Synthesis"
  11. Bosken YK, Cholko T, Lou YC, (Wu KP), Chang CA  (2020-08)  Frontiers in Molecular Biosciences  7, 174  "Insights Into Dynamics of Inhibitor and Ubiquitin-Like Protein Binding in SARS-CoV-2 Papain-Like Protease"
  12. Yang TJ, Chang YC, Ko TP, Draczkowski P, Chien YC, Chang YC, (Wu KP), Khoo KH, Chang HW, Hsu STD  (2020-01)  Proceedings of the National Academy of Sciences of the United States of America  117(3), 1438-1446  "Cryo-EM analysis of a feline coronavirus spike protein reveals a unique structure and camouflaging glycans."
  13. Qiu Y, Zheng Y, (Wu KP), Schulman BA  (2017)  Protein science : a publication of the Protein Society  26(8), 1674-1680  "Insights into links between autophagy and the ubiquitin system from the structure of LC3B bound to the LIR motif from the E3 ligase NEDD4."
  14. Mulder MP, Witting K, Berlin I, Pruneda JN, (Wu KP), Chang JG, Merkx R, Bialas J, Groettrup M, Vertegaal AC, Schulman BA, Komander D, Neefjes J, El Oualid F, Ovaa H  (2016-07)  Nature chemical biology  12(7), 523-530  "A cascading activity-based probe sequentially targets E1-E2-E3 ubiquitin enzymes."
  15. Brown NG, VanderLinden R, Watson ER, Weissmann F, Ordureau A, (Wu KP), Zhang W, Yu S, Mercredi PY, Harrison JS, Davidson IF, Qiao R, Lu Y, Dube P, Brunner MR, Grace CRR, Miller DJ, Haselbach D, Jarvis MA, Yamaguchi M, Yanishevski D, Petzold G, Sidhu SS, Kuhlman B, Kirschner MW, Harper JW, Peters JM, Stark H, Schulman BA  (2016-06)  Cell  165(6), 1440-1453  "Dual RING E3 Architectures Regulate Multiubiquitination and Ubiquitin Chain Elongation by APC/C."
  16. Zhang W, (Wu KP), Sartori MA, Kamadurai HB, Ordureau A, Jiang C, Mercredi PY, Murchie R, Hu J, Persaud A, Mukherjee M, Li N, Doye A, Walker JR, Sheng Y, Hao Z, Li Y, Brown KR, Lemichez E, Chen J, Tong Y, Harper JW, Moffat J, Rotin D, Schulman BA, Sidhu SS  (2016-04)  Molecular cell  62(1), 121-136  "System-Wide Modulation of HECT E3 Ligases with Selective Ubiquitin Variant Probes."
  17. Fang NN, Zhu M, Rose A, (Wu KP), Mayor T  (2016)  Nature communications  7, 12907  "Deubiquitinase activity is required for the proteasomal degradation of misfolded cytosolic proteins upon heat-stress."
  18. Janowska MK, (Wu KP), Baum J  (2015-10)  Scientific reports  5, 15164  "Unveiling transient protein-protein interactions that modulate inhibition of alpha-synuclein aggregation by beta-synuclein, a pre-synaptic protein that co-localizes with alpha-synuclein."
  19. Riling C, Kamadurai H, Kumar S, O'Leary CE, (Wu KP), Manion EE, Ying M, Schulman BA, Oliver PM  (2015)  The Journal of biological chemistry  290(39), 23875-87  "Itch WW Domains Inhibit Its E3 Ubiquitin Ligase Activity by Blocking E2-E3 Ligase Trans-thiolation."
  20. Kim S, (Wu KP), Baum J  (2013-03)  Journal of biomolecular NMR  55(3), 249-256  "Fast hydrogen exchange affects (1)(5)N relaxation measurements in intrinsically disordered proteins."
  21. Park JH, Yoshizumi S, Yamaguchi Y, (Wu KP), Inouye M  (2013)  Proteins  81(5), 874-83  "ACA-specific RNA sequence recognition is acquired via the loop 2 region of MazF mRNA interferase."
  22. Narayanan C, Weinstock DS, (Wu KP), Baum J, Levy RM  (2012)  Journal of chemical theory and computation  8(10), 3929-3942  "Investigation of the Polymeric Properties of alpha-Synuclein and Comparison with NMR Experiments: A Replica Exchange Molecular Dynamics Study."
  23. Kobayashi H, Swapna GV, (Wu KP), Afinogenova Y, Conover K, Mao B, Montelione GT, Inouye M  (2012)  Journal of biomolecular NMR  52(4), 303-13  "Segmental isotope labeling of proteins for NMR structural study using a protein S tag for higher expression and solubility."
  24. Masuda H, Tan Q, Awano N, (Wu KP), Inouye M  (2012)  Molecular microbiology  84(5), 979-89  "YeeU enhances the bundling of cytoskeletal polymers of MreB and FtsZ, antagonizing the CbtA (YeeV) toxicity in Escherichia coli."
  25. (Wu KP), Baum J  (2011)  Biomolecular NMR assignments  5(1), 43-6  "Backbone assignment and dynamics of human alpha-synuclein in viscous 2 M glucose solution."
  26. Kang L, (Wu KP), Vendruscolo M, Baum J  (2011)  Journal of the American Chemical Society  133(34), 13465-70  "The A53T mutation is key in defining the differences in the aggregation kinetics of human and mouse alpha-synuclein."
  27. (Wu KP), Baum J  (2010-04)  Journal of the American Chemical Society  132(16), 5546-5547  "Detection of transient interchain interactions in the intrinsically disordered protein alpha-synuclein by NMR paramagnetic relaxation enhancement."
  28. (Wu KP), Weinstock DS, Narayanan C, Levy RM, Baum J  (2009-08)  Journal of molecular biology  391(4), 784-796  "Structural reorganization of alpha-synuclein at low pH observed by NMR and REMD simulations."
  29. (Wu KP), Kim S, Fela DA, Baum J  (2008)  Journal of molecular biology  378(5), 1104-15  "Characterization of conformational and dynamic properties of natively unfolded human and mouse alpha-synuclein ensembles by NMR: implication for aggregation."
  30. Weinstock DS, Narayanan C, Felts AK, Andrec M, Levy RM, (Wu KP), Baum J  (2007)  Journal of the American Chemical Society  129(16), 4858-9  "Distinguishing among structural ensembles of the GB1 peptide: REMD simulations and NMR experiments."
  31. Pan YR, Wu KP, Lou YC, Liao YD, Chen C  (2005)  Journal of biomolecular NMR  31(2), 175-6  "1H, 13C and 15N resonance assignments and secondary structure of murine angiogenin 4."
  32. Wang I, Lou YC, (Wu KP), Wu SH, Chang WC, Chen C  (2005)  Journal of molecular biology  346(4), 1071-82  "Novel solution structure of porcine beta-microseminoprotein."
  33. (Wu KP), Wu CW, Tsao YP, Kuo TW, Lou YC, Lin CW, Wu SC, Cheng JW  (2003)  The Journal of biological chemistry  278(46), 46007-13  "Structural basis of a flavivirus recognized by its neutralizing antibody: solution structure of the domain III of the Japanese encephalitis virus envelope protein."