Research

Protein ubiquitination, amyloidosis and drug discovery of the related diseases

Our research focuses on two topics:
(1) Protein ubiquitination and linked human diseases
Post-translational modifications (PTMs) are important biological processes related to numerous cellular molecular events such as cell division, signaling ,and protein turnover. Ubiquitination is one of the post-translational modifications which employs a 76-residue small protein called ubiquitin to modify substrate proteins. Nearly half of human proteins are involved in the ubiquitination proteasome system and (mis-)regulated ubiquitinations are frequently correlated with human diseases.

We want to unravel the relationship of protein ubiquitination (or ISGylation) and infectious diseases such as SARS, Dengue fever, influenza, and Tuberculosis. These infections often substantially alter the cellular ubiquitin homeostasis hence suppress innate immunity. We employ biophysics, structural biology, biochemistry, and synthetic biology approaches to understand the infection-caused (de-)ubiquitination mechanism. By holding the knowledge, we aim to develop inhibitors against infections and enhance immunity.

(2) Protein amyloidosis and its impact on neurodegenerative diseases
The aggregated proteins called amyloid residing in the neuron cell frequently link to many neurodegenerative diseases. Parkinson’s disease is a prevalent neurodegenerative disease second to Alzheimer’s disease. There are many factors associated with Parkinson’s disease; and one hallmark is the amyloidosis of alpha-synuclein. Familial mutations, environmental factors, and foods could be the root causes of amyloidosis of alpha-synuclein. We are working on deciphering the mystery of interconversion of alpha-synuclein from intrinsically disordered protein to ordered cross-beta fibrils. By understanding the mechanism, we will have the opportunity to retard and even reverse the aggregation inside neuron cells.

Degrees and Positions Held
Positions Held
  • 2018 – present   Assistant Research Fellow, Institute of Biological Chemistry, Academia Sinica, Taiwan
  • 2018 – 2018   Visiting Assistant Professor, Institute of Biological Chemistry, Academia Sinica, Taiwan
  • 2017 – 2018   Assistant research fellow, MOST
  • 2012 – 2017   Postdoc, Department of Structural Biology, St Jude Children’s Research Hospital, USA
  • 2010 – 2012   Postdoc, Center for Advanced Biotechnology and Medicine, Rutgers, the State University of New Jersey, USA
Degrees
  • 2004 – 2010   Ph.D., Chemistry and Chemical Biology, Rutgers, the State University of New Jersey, USA
  • 2000 – 2002   M.S., Life Sciences, National Tsing Hua University, Taiwan
  • 1996 – 2000   B.S., Life Sciences, National Tsing Hua University, Taiwan
Selected Publications
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)
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)
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)
Janowska MK, Wu KP, Baum J
Scientific Reports (2015)
Kim S, Wu KP, Baum J
Journal of Biomolecular NMR (2013)
Wu KP, Baum J
Journal of American Chemistry Society (2010)
Wu KP, Weinstock DS, Narayanan C, Levy RM, Baum J
Journal of Molecular Biology (2009)
Publications List
  1. 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"
  2. 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"
  3. 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."
  4. 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."
  5. 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."
  6. 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."
  7. 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."
  8. 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."
  9. 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."
  10. 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."
  11. 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."
  12. 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."
  13. 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."
  14. 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."
  15. 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."
  16. (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."
  17. 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."
  18. (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."
  19. (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."
  20. (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."
  21. 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."
  22. 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."
  23. 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."
  24. (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."

Protein ubiquitination, amyloidosis and drug discovery of the related diseases

Our research focuses on two topics:
(1) Protein ubiquitination and linked human diseases
Post-translational modifications (PTMs) are important biological processes related to numerous cellular molecular events such as cell division, signaling ,and protein turnover. Ubiquitination is one of the post-translational modifications which employs a 76-residue small protein called ubiquitin to modify substrate proteins. Nearly half of human proteins are involved in the ubiquitination proteasome system and (mis-)regulated ubiquitinations are frequently correlated with human diseases.

We want to unravel the relationship of protein ubiquitination (or ISGylation) and infectious diseases such as SARS, Dengue fever, influenza, and Tuberculosis. These infections often substantially alter the cellular ubiquitin homeostasis hence suppress innate immunity. We employ biophysics, structural biology, biochemistry, and synthetic biology approaches to understand the infection-caused (de-)ubiquitination mechanism. By holding the knowledge, we aim to develop inhibitors against infections and enhance immunity.

(2) Protein amyloidosis and its impact on neurodegenerative diseases
The aggregated proteins called amyloid residing in the neuron cell frequently link to many neurodegenerative diseases. Parkinson’s disease is a prevalent neurodegenerative disease second to Alzheimer’s disease. There are many factors associated with Parkinson’s disease; and one hallmark is the amyloidosis of alpha-synuclein. Familial mutations, environmental factors, and foods could be the root causes of amyloidosis of alpha-synuclein. We are working on deciphering the mystery of interconversion of alpha-synuclein from intrinsically disordered protein to ordered cross-beta fibrils. By understanding the mechanism, we will have the opportunity to retard and even reverse the aggregation inside neuron cells.

Positions Held
  • 2018 – present   Assistant Research Fellow, Institute of Biological Chemistry, Academia Sinica, Taiwan
  • 2018 – 2018   Visiting Assistant Professor, Institute of Biological Chemistry, Academia Sinica, Taiwan
  • 2017 – 2018   Assistant research fellow, MOST
  • 2012 – 2017   Postdoc, Department of Structural Biology, St Jude Children’s Research Hospital, USA
  • 2010 – 2012   Postdoc, Center for Advanced Biotechnology and Medicine, Rutgers, the State University of New Jersey, USA
Degrees
  • 2004 – 2010   Ph.D., Chemistry and Chemical Biology, Rutgers, the State University of New Jersey, USA
  • 2000 – 2002   M.S., Life Sciences, National Tsing Hua University, Taiwan
  • 1996 – 2000   B.S., Life Sciences, National Tsing Hua University, Taiwan
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)
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)
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)
Janowska MK, Wu KP, Baum J
Scientific Reports (2015)
Kim S, Wu KP, Baum J
Journal of Biomolecular NMR (2013)
Wu KP, Baum J
Journal of American Chemistry Society (2010)
Wu KP, Weinstock DS, Narayanan C, Levy RM, Baum J
Journal of Molecular Biology (2009)
  1. 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"
  2. 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"
  3. 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."
  4. 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."
  5. 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."
  6. 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."
  7. 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."
  8. 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."
  9. 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."
  10. 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."
  11. 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."
  12. 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."
  13. 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."
  14. 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."
  15. 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."
  16. (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."
  17. 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."
  18. (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."
  19. (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."
  20. (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."
  21. 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."
  22. 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."
  23. 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."
  24. (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."