Principal Investigator, Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences.

Postdoctoral Fellow, 2008-2013. University of California, Los Angeles. USA.

Ph.D., 2002-2008.  Peking University. China

B.S., 1998-2002.  Jilin University. China

The research of Liu laboratory focuses on the mechanisms of protein phase separation and pathological protein aggregation in neurodegenerative diseases (NDs). The key pathological hallmarks of neurodegenerative diseases are the formation and accumulation of misfolded proteins, that were previously only known to be consisted of β-sheet rich forms of proteins with self-assembly and self-propagation properties similar to that of prions. Using exciting new technologies that were developed in his lab, Dr. Liu made a series of interesting and surprisingly systematic discoveries on the mechanisms of amyloid protein structure, formation, propagation and neurodegeneration. Studying amyloid structures are highly challenging and require special expertise: currently there are only a handful labs around the world that can do this. To overcome the existing technological limitations for studying the structures of amyloid fibers, Dr. Liu developed cryo-EM based helical 3D reconstruction method and electron diffraction method for nano-sized 3D crystals (micro-ED) which can overcome the technical challenges due to the tiny sizes of amyloid crystals and insoluble nature of amyloid fibrils. These new technologies advanced our ability to decipher the structures of pathological proteins in the misfolded amyloid fibrillar state which is not accessible by traditional structural biology tools. Using these technologies, Dr. Liu discovered that the atomic structures of protein amyloids are much more complex and dynamic than previously appreciated. He revealed the surprising dynamic structural polymorphs of pathological amyloid fibrils (e.g. α-synuclein and FUS), and uncovered the fundamental principles of protein folding in pathological fibrillar state which is distinct from the proteins in native state.  He discovered that different polymorphic fibrils exhibit distinct pathological properties, which provides a framework for us to further explore the mechanisms of the clinicopathological heterogeneity of PD and other neurodegenerative disorders and has important implications for developing therapeutic strategies. Furthermore, he discovered that the dynamic structural polymorphs of pathological amyloid fibril are subject to posttranslational modifications including phosphorylation, PARylation, and molecular chaperones (Hsp27, Hsp40) which have important impact on the stability and pathological properties of amyloids. Taken together, by combining interdisciplinary chemical and biological approaches, Dr. Liu revealed the structural basis of protein pathological aggregation in NDs, demonstrated the regulatory mechanisms of protein aggregation by disease-related post-translational modification, developed new strategies of designing small molecules to modulate protein phase separation for therapeutic application. 

In the past 5 years, as the corresponding or co-corresponding author, Dr. Liu published over 40 SCI papers, including Cell, PNAS (6), Nat Struct & Mol Biol (3), JACS, Cell Research (5), Nat Commun (7), Angew, Mol Cell, Dev Cell, and Sci Adv. His systematical findings on protein phase separation and aggregation in NDs have been well recognized internationally in the field, and he has been invited by Nat Chem Biol and Nat Rev Neurosci to write reviewing articles for introducing the structural polymorphism of amyloid aggregation and its hierarchical chemical determination in NDs. Dr. Liu’s work is supported by several highly competitive grants including the Key project of the Natural Science Foundation of China, the Major State Basic Research Development Program, the National 863 Major Scientific Project, overseas high-level talents, Shanghai outstanding academic leaders. Dr. Liu has also been invited to give presentations in EMBL/EMBO meetings, Gordon conference, and has been served as an international reviewer for foundations of Medical Research Council (MRC, UK), European Research Council (ERC) and others.

Significant Works

1.       Conformational strains of pathogenic amyloid proteins in neurodegenerative diseases. Liu D*, Liu C*.  Nature Reviews Neuroscience (2022), doi: 10.1038/s41583-022-00603-7. Online ahead of print. (Invited review).

2.       Heparin induces α-synuclein to form new fibril polymorphs with attenuated neuropathology. Tao Y, Sun Y, Lv S, Xia, W, Zhao K, Xu Q, Zhao Q, Le W, Wang Y, Liu C*, Li D*. Nature Communications (2022),13(1):4226.

3.       Cryo-EM structure of an amyloid fibril formed by full-length human SOD1 reveals its conformational conversion. Wang LQ, Ma Y, Yuan HY, Zhao K, Zhang MY, Wang Q, Huang X, Xu WC, Dai B, Chen J, Li D, Zhang D, Wang Z, Zou L, Yin P, Liu C*, Liang Y*.

Nature Communications (2022), 13(1):3491.

4.       Liquid-liquid phase separation of RBGD2/4 is required for heat stress resistance in Arabidopsis. Zhu S, Gu J, Yao J, Li Y, Zhang Z, Xia W, Wang Z, Gui X, Li L, Li D, Zhang H*, Liu C*.  Dev Cell. (2022), 57(5):583-597.

5.       Generic amyloid fibrillation of TMEM106B in patient with Parkinson's disease dementia and normal elders. Fan Y, Zhao Q, Xia W, Tao Y, Yu W, Chen M, Liu Y, Zhao J, Shen Y, Sun Y, Si C, Zhang S, Zhang Y, Li W, Liu C*, Wang J*, Li D*. Cell Research (2022);32(6):585-588.

6.       A high-throughput method for exploring the parameter space of protein liquid-liquid phase separation. Li Y, Gu, J, Liu C*, Li D*. Cell Reports Physical Science (2022), 3(3), 100764,

7.       Molecular structure of an amyloid fibril formed by FUS low-complexity domain. Sun Y, Zhang S, Hu J, Tao Y, Xia W, Gu J, Li Y, Cao Q, Li D, Liu C*.  iScience (2021), 25(1): 103701.

8.       O-Glycosylation Induces Amyloid-β To Form New Fibril Polymorphs Vulnerable for Degradation. Liu D, Wei Q, Xia W, He C, Zhang Q, Huang L, Wang X, Sun Y, Ma Y, Zhang X, Wang Y, Shi X, Liu C*, Dong S*.  J Am Chem Soc. (2021), 143(48):20216-20223.

9.       The hereditary mutation G51D unlocks a distinct fibril strain transmissible to wild-type α-synuclein. Sun Y, Long H, Xia W, Wang K, Zhang X, Sun B, Cao Q, Zhang Y, Dai B, Li D, Liu C*.  Nature Communications (2021), 12(1):6252

10.   Spatiotemporal dynamic regulation of membraneless organelles by chaperone networks. Li D*, Liu C*. Trends Cell Biol. (2021). S0962-8924(21)00165-3. (Invited forum).

11.   Genetic prion disease-related mutation E196K displays a novel amyloid fibril structure revealed by cryo-EM. Wang LQ, Zhao K, Yuan HY, Li XN, Dang HB, Ma Y, Wang Q, Wang C, Sun Y, Chen J, Li D, Zhang D, Yin P, Liu C*, Liang Y*. Science Advances (2021). 7(37): eabg9676.

12.   Hsp70 chaperones TDP-43 in dynamic, liquid-like phase and prevents it from amyloid aggregation Gu J.G, Wang C, Hu R, Li Y, Zhang S, Sun Y, Wang Q, Li D, Fang Y*, Liu C* Cell Research (2021). 31(9):1024-1027.

13.   Mechanistic basis for receptor-mediated pathological α-synuclein fibril cell-to-cell transmission in Parkinson's disease. Zhang S, Liu Y, Jia C, Lim Y Feng G, Xu E, Long H, Yasuyoshi K, Tao Y, Zhao C, Wang C, Liu Z, Hu J, Ma M, Liu Z, Lin J, Li D, Wang R, Dawson V, Dawson T*, Li Y*, Mao X*, Liu C*. Proc. Natl. Acad. Sci. U S A. (2021). 118(26): e2011196118.

14.   Wild-type α-synuclein inherits the structure and exacerbated neuropathology of E46K mutant fibril strain by cross-seeding. Long H.F., Zheng W, Liu Y, Sun Y, Zhao K, Liu Z, Xia W, Lv S, Liu Z, Li D., He K.*, Liu C*. Proc. Natl. Acad. Sci. U S A. (2021). 118(20):e2012435118.

15.   The structure of a minimum amyloid fibril core formed by necroptosis-mediating RHIM of human RIPK3. Wu X, Ma Y, Zhao K, Zhang J, Sun Y, Li Y, Dong X, Hu H, Liu J, Wang J, Zhang X, Li B, Wang H, Li D, Sun B, Lu J*, Liu C*. Proc. Natl. Acad. Sci. U S A. (2021). 118(14):e2022933118.

16.   Hierarchical chemical determination of amyloid polymorphs in neurodegenerative disease.  Li D*, Liu C*. Nature Chemical Biology (2021). 17(3):237-245. (Invited review).

17.   The nuclear localization sequence mediates hnRNPA1 amyloid fibril formation revealed by cryoEM structure. Sun Y, Zhao K, Xia W, Feng G, Gu J, Ma Y, Gui X, Zhang X, Fang Y, Sun B, Wang R, Liu C*, Li D. Nature Communications (2020). 11(1):6349.

18.   Hsp40 proteins phase separate to chaperone the assembly and maintenance of membraneless organelles. Gu J, Liu Z, Zhang S, Li Y, Xia W, Wang C, Xiang H, Liu Z, Tan L, Fang Y, Liu C*, Li D*.  Proc Natl Acad Sci U S A. (2020). 117(49):31123-31133.

19.   Phase separation of protein tyrosine phosphatase underlies MAPK hyperactivation by disease-associated SHP2 mutants.  Zhu G, Xie J, Kong W, Xie J, Li Y, Du L, Zheng Q, Sun L, Guan M, Li H, Zhu T, He H, Liu Z, Xia X, Kan C, Tao Y, Shen H, Li D, Wang S, Yu Y, Yu Z, Zhang Z, Liu C*, Zhu J*.  Cell (2020). 183(2):490-502.e18.

20.   Stress Induces Dynamic, Cytotoxicity-Antagonizing TDP-43 Nuclear Bodies via Paraspeckle LncRNA NEAT1-Mediated Liquid-Liquid Phase Separation. Wang C, Duan Y, Duan G, Wang Q, Zhang K, Deng X, Qian B, Gu J, Ma Z, Zhang S, Guo L, Liu C*, Fang Y*.   Mol Cell. (2020). 79(3):443-458.e7

21.   Parkinson's disease-related phosphorylation at Tyr39 rearranges α-synuclein amyloid fibril structure revealed by cryo-EM. Zhao K, Lim YJ, Liu Z, Long H, Sun Y, Hu JJ, Zhao C, Tao Y, Zhang X, Li D, Li YM*, Liu C*.  Proc Natl Acad Sci U S A. (2020). 117(33): 20305-20315.

22.   Hsp27 chaperones FUS phase separation under the modulation of stress-induced phosphorylation. Liu Z.Y., Zhang S, Gu J, Tong Y, Li Y, Gui X, Long H, Wang C, Zhao C, Lu J, He L, Li Y, Liu Z, Li D*, Liu C*.  Nature Structural & Molecular Biology (2020). 27(4):363-372.

23.   Cryo-EM structure of an amyloid fibril formed by full-length human prion protein. Wang L.Q., Zhao K, Yuan H, Wang Q, Guan Z, Tao J, Li L, Sun Y, Yi C, Chen J, Li D, Zhang D, Yin P, Liu C*, Liang Y*.  Nature Structural & Molecular Biology (2020). 27(6):598-602.

24.   Different regions of synaptic vesicle membrane regulate VAMP2 conformation for the SNARE assembly. Wang C, Tu J, Zhang S, Cai B, Liu Z, Hou S, Zhong Q, Hu X, Liu W, Li G, Liu Z, He L, Diao J, Zhu Z, Li D.*, Liu C*.  Nature Communications (2020). 11(1):1531.

25.   Parkinson’s disease associated mutation E46K of α-synuclein triggers the formation of a novel fibril structure. Zhao K, Li Y, Liu Z, Long H, Zhao C, Luo F, Sun Y, Tao Y, Su X, Li D*, Li X*, Liu C*.  Nature Communications (2020). 11(1):2643.

26.   Nicotinamide mononucleotide adenylyltransferase uses its NAD+ substrate-binding site to chaperone phosphorylated Tau. Ma X, Zhu Y, Lu J, Xie J, Li C, Shin C, Qiang J, Liu J, Dou S, Xiao Y, Wang C, Jia C, Long H, Yang J, Fang Y, Jiang L, Zhang Y, Zhang S, Zhai G*, Liu C*, Li D*.  eLife (2020). 9, e51859.

27.   Cryo-EM structure of full-length α-synuclein amyloid fibril with Parkinson's disease familial A53T mutation. Sun Y.P., Hou S.Q., Zhao K., Long H.F., Liu Z.Y., Gao J., Zhang Y.Y., Su X.D., Li D.*, Liu C*. Cell Research (2020). (4):360-362.

28.   Structural basis for reversible amyloids of hnRNPA1 elucidates their role in stress granule assembly. Gui X, Luo F, Li Y, Zhou H, Qin Z, Liu Z, Gu J, Xie M, Zhao K, Dai B, Shin W, He J, He L, Jiang L, Zhao M, Sun B, Li X.M, Liu C*, Li D* Nature Communications (2019). (1), 2006.

29.   PARylation regulates stress granule dynamics, phase separation, and neurotoxicity of disease-related RNA-binding proteins. Duan Y, Du A, Gu J, Duan G, Wang C, Gui X, Ma Z, Qian B, Deng X, Zhang K, Sun L, Tian K, Zhang Y, Jiang H, Liu C*, Fang Y*.  Cell Research, (2019). Mar;29(3):233-247.

30.   Better Together: A Hybrid Amyloid Signals Necroptosis. Li D*, Liu C*.  Cell (2018). 173(5):1068-1070 (Invited preview)

31.   Amyloid fibril structure of α-synuclein determined by cryo-electron microscopy. Li Y, Zhao C, Luo F, Liu Z, Gui X, Luo Z, Zhang X, Li D*, Liu C*, Li X* Cell Research (2018). (9):897-903

32.   Atomic structures of two segments from FUS LC domain reveal reversible amyloid fibril formation. Luo F, Gui X, Zhou H, Gu J, Li Y, Liu X, Zhao M, Li D*, Li X*, and Liu C*.  Nature Structural & Molecular Biology (2018). 25, 341-346.

33.   Tunable assembly of amyloid-forming peptides into nanosheets as a retrovirus carrier. Dai B, Li D, Xi W, Luo, F, Zhang, X, Zou, M, Cao, M, Hu J, Wang W, Wei G*; Zhang Y*, Liu C*.  Proc. Natl. Acad. Sci. U S A. (2015). 112 (10), 2996.