Principal Investigators +886-2-27855696,5070
Room 507, IBC, AS


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

  • 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
  • 2024 – present   Associate Research Fellow, Institute of Biological Chemistry, Academia Sinica, Taiwan
  • 2018 – 2024   Assistant Research Fellow, 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

Selected Publications

What strengthens Protein-Protein Interactions: Analysis and Applications of Residue Correlation Networks. 
Hung TI, Hsieh YJ, Lu WL, Wu KP*, Chang CA*  
Journal of Molecular Biology (2023)

Structural basis of transcriptional activation by the OmpR/PhoB-family response regulator PmrA.  
Lou YC*, Huang HY, Yeh HH, Chiang WH, Chen C*, Wu KP*  
Nucleic Acids Research (2023)

Robust Design of Effective Allosteric Activators for Rsp5 E3 Ligase Using the Machine Learning Tool ProteinMPNN.  
Kao HW, Lu WL, Ho MR, Lin YF, Hsieh YJ, Ko TP, Hsu STD, Wu KP*  
ACS Synthetic Biology (2023)

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)

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)

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)

Publication List