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Major Research Interests

Protein Biophysics with Experimental and Computational Approaches; Molecular Mechanisms for Protein Aggregation and its Cytotoxicity in Diseases and Aging; Intrinsically Disordered Proteins; Structures and Dynamics of Membrane-interacting Proteins; Molecular Virology; Drug Discovery from Natural Products; Structure- and Dynamics-driven Drug Design.

Major Research Projects

1. Fundamental mechanisms underlying protein folding, structure, dynamics and aggregation by NMR spectroscopy, X-ray crystallography and molecular dynamics (MD) simulation, as well as their linkages to aging and diseases, in particular amyotrophic lateral sclerosis (ALS).

2. In 2005, we discovered that previously-thought “insoluble proteins” could marvellously be solubilized in pure water. This discovery has now been extensively used by other groups worldwide, and also offers ourselves an unprecedented avenue to decipher the mechanism manifesting cellular toxicity of the aggregation-proton proteins. For example, we recently decoded that the aggregation-prone TDP-43 N-terminus encodes a novel ubiquitin-like fold and its unfolded form in equilibrium that can be shifted by binding to nucleic acids, thus providing critical insights into normal TDP-43 functions as well as its aggregation found in ∼97% ALS and ∼45% FTD patients. Most recently, we determined the structure of TDP-43 prion-like domain which hosts almost all ALS-causing mutations. Our studies revealed a mechanism by which ALS-causing mutations exaggerate the formation of amyloid structures of TDP-43.

3. Fundamentally, we deciphered that the driving forces for protein aggregation and interaction with membranes are at least partly overlapped, or even two sides of the same coin. For example, ALS-causing mutations rendered the highly-soluble cytosolic MSP and SOD1 to become insoluble forms, which suddenly transform into helical membrane proteins. Most recently, we also decoded that the nascent wild-type (WT) SOD1 can interact with membranes to transform into a helical conformation very similar to that by the ALS-causing mutant SOD1, thus implying that familial ALS caused by mutant SOD1 and sporadic ALS by WT SOD1 may converge on abnormally interacting with membranes.

4. Design of small molecules targeting EphA4 receptor, the only known ALS modifier. We revealed that two small molecules induced opposite signaling outcomes of EphA4 by triggering different dynamics.

Representative Publications

(*,corresponding author)

1. Lim L, Wei Y, Lu Y, Song J*. ALS-Causing Mutations Significantly Perturb the Self-Assembly and Interaction with Nucleic Acid of the Intrinsically Disordered Prion-Like Domain of TDP-43. PLoS Biol. 2016; 14:e1002338. (reported by >100 international media)

2. Lim L, Song J*. SALS-linked WT-SOD1 adopts a highly similar helical conformation as FALS-causing L126Z-SOD1 in a membrane environment. Biochim Biophys Acta (Biomembranes). 2016; 1858:2223-30.

3. Qin H, Lim LZ, Song J*. Dynamic Principle for Designing Antagonistic/Agonistic Molecules for EphA4 Receptor, the Only Known ALS Modifier. ACS Chem Biol. 2015; 10:372-8.

4. Lim L, Lee X, Song J*. Mechanism for transforming cytosolic SOD1 into integral membrane proteins of organelles by ALS-causing mutations. Biochim Biophys Acta (Biomembranes). 2015; 1848:1-7.

5. Qin H, Lim LZ, Wei Y, Song J*. TDP-43 N terminus encodes a novel ubiquitin-like fold and its unfolded form in equilibrium that can be shifted by binding to ssDNA. Proc Natl Acad Sci U S A. 2014; 111:18619-24. (reported by international media)

6. Theng SS, Wang W, Mah WC, Chan C, Zhuo J, Gao Y, Qin H, Lim L, Chong SS, Song J*, Lee CG. Disruption of FAT10- MAD2 binding inhibits tumor progression. Proc Natl Acad Sci U S A. 2014; 111:E5282-91. (reported by international media)

7. Song J*. Why do proteins aggregate? “Intrinsically insoluble proteins” and “dark mediators” revealed by studies on “insoluble proteins” solubilized in pure water. F1000Res. 2013; 2:94.

8. Qin H, Lim L, Song J*. Protein dynamics at Eph receptor-ligand interfaces as revealed by crystallography, NMR and MD simulations. BMC Biophys. 2012; 5: 2. (Recommended by Faculty 1000)

9. Shi J, Han N, Lim L, Lua S, Sivaraman J. Wang L, Mu Y, Song J*. Dynamically-Driven Inactivation of the Catalytic Machinery of the SARS 3C-Like Protease by the N214A Mutation on the Extra Domain. PLoS Computational Biology. 2011; 7: e1001084.

10. Qin H, Noberini R, Huan X, Shi J, Pasquale EB, Song J*. Structural characterization of the EphA4-Ephrin-B2 complex reveals new features enabling Eph-ephrin binding promiscuity. J Biol Chem. 2010; 285:644-54.

11. Shi J, Lua S., Tong J. and Song J*. Elimination of the Native Structure and Solubility of the hVAPB MSP Domain by the Pro56Ser Mutation which Causes Amyotrophic Lateral Sclerosis. Biochemistry. 2010; 49: 3887-3897.

12. Song J*. Insight into “Insoluble Proteins” with Pure Water. FEBS Lett. 2009; 6: 953-959. (Recommended by Faculty 1000)

13. Liu J, Song J*. NMR evidence for forming highly populated helical conformations in the partially folded hNck2 SH3 domain. Biophys J. 2008; 95: 4803-4812.

14. Qin H, Shi J, Noberini R, Pasquale EB, Song J*. Crystal Structure and NMR Binding Reveal That Two Small Molecule Antagonists Target the High Affinity Ephrin-binding Channel of the EphA4 Receptor. J Biol Chem. 2008; 283:29473-29484.

15. Shi J, Sivaraman J, Song J*. Mechanism for Controlling Dimer-monomer Switch and Coupling Dimerization to Catalysis of the SARS-CoV 3C-Like Protease. J. Virol. 2008; 82: 4620-462

16. Li M, Liu J, Ran X, Fang M, Shi J, Qin H, Goh J-M, and Song J*. Resurrecting Abandoned Proteins with Pure Water: CD and NMR Studies of Protein Fragments Solubilized in Salt-Free Water. Biophys. J. 2006; 91: 4201-4209.

17. Wei Z, Song J*. Molecular mechanism underlying the thermal stability and pH-Induced unfolding of CHABII. J. Mol. Biol. 2005; 348: 205-218.

18. Ran X, Song J*. Structural Insight into the Binding Diversity between the Tyr-Phosphorylated Human EphrinBs and Nck2 SH2 Domain. J. Biol. Chem. 2005; 280:19205-19212.

19. Shi J, Wei Z, Song J*. Dissection study on the SARS 3C-like protease reveals the critical role of the extra domain in dimerization of the enzyme: Defining the extra domain as a new target for design of highly- specific protease inhibitors. J Biol Chem. 2004; 279: 24765-24773.

20. Song J*. Tyrosine phosphorylation of the well packed ephrinB cytoplasmic beta-hairpin for reverse signaling. structural consequences and binding properties. J Biol Chem. 2003; 278: 24714-24720.