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University of Colorado Department of Biochemistry and Molecular Genetics

Biochemistry and Molecular Genetics
 

Changwei Liu, PhD

Associate Professor


Ph.D., Chinese Academy of Sciences

Contact Information:

Phone: (303) 724-3208
E-mail: Changwei.Liu@ucdenver.edu

Postdoctoral Positions Available


Graduate Program Memberships

Molecular Biology​
Biomedical Sciences
MSTP
Structural Biology & Biochemistry

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Deubiquitinating Enzymes: From Basic Research to Translational Studies 

Our lab is interested in the study of deubiquitinating enzymes (DUBs). Human cells have approximately 100 DUBs that function to antagonize protein ubiquitination.  Ubiquitin is a 76 amino acid protein that can be conjugated on the majority of cellular proteins through a cascade of enzymatic reactions catalyzed by a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2) and a ubiquitin ligase (E3), through which ubiquitin can be covalently conjugated on substrate proteins as a monomer (monoubiquitination) or polymer (polyubiquitination). Protein ubiquitination can target proteins to the 26S proteasome for degradation (usually requiring polyubiquitination) or function as a non-degradative signal for mediating protein trafficking or altering enzyme activity, by which protein ubiquitination regulates nearly all cellular procedures. Similar to many other posttranslational modifications, protein ubiquitination is highly dynamic in the cell, counteracted by degradation and deubiquitination. DUBs are responsible for deubiquitination of proteins, thereby functioning to reverse/balance various signaling mediated by ubiquitination.  Currently, we are investigating several DUBs in the ubiquitin-specific protease (USP) family, including USP9X, USP16 and USP35.  Our current projects include:

1)      Investigating functions of DUBs in regulating cellular signaling.  We use proteomics, biochemical and cell biological approaches to identify novel substrates of DUBs and then perform mechanistic studies to understand how deubiquitination of these substrate proteins regulates their protein stability, cellular localization and functions.  For instance, we are investigating the roles of our interested DUBs in regulating signaling transduction in primary cilium, insulin signaling, stress-induced translation and apoptosis.

2)      Determining high-resolution structures of DUBs using single particle Cryo EM.  USP9X is one of the largest DUBs with a molecular weight of ~280 kDa. Both USP16 (93 kDa) and USP35 (113 kDa) form large oligomers. We collaborate with my colleagues using our state-of-the-art single particle cryo EM facility to determine high-resolution structures of these DUBs and complexes between DUBs and their substrates. With high-resolution structures, we hope to understand i) the detailed structure arrangements of these DUBs; ii) if activation of these DUBs is regulated, such as through its tertiary/quaternary structures; and iii) how these DUBs recognize its substrates.

3)      Develop drug-like chemical inhibitors of DUBs for cancer therapy.  DUBs are potential drug targets and biomarkers for human disease treatment and diagnosis, especially in cancer. The USP DUBs are cysteine proteases that have been successfully targeted by small chemicals. We collaborate with drug discovery core facilities to use high throughput screening and medicinal chemistry development to develop drug-like chemical compounds that inhibit the deubiquitinating activity of our interested DUBs. Structural studies will be applied to determine how these chemical inhibitors inhibit DUBs. We will use these novel chemical inhibitors to investigate the biological functions of the corresponding DUBs, to evaluate their anticancer efficacy in cancer cell lines, human cancer xenografts and hopefully in clinical trials.  




Current Lab Colleagues​

 Results From Research : Selected site and subsites
PicturesLast NameFirst NameJob TitleEmailBio Page
HanKe-JunPostdoctoral FellowKe-Jun.Han@UCDenver.edu  
JacobsonAndrewPostdoctoral FellowAndrew.Jacobson@UCDenver.edu  
TianWenminPostdoctoral FellowWenmin.Tian@UCDenver.edu