Biography

View Research Profile

Bibliography: https://www.ncbi.nlm.nih.gov/myncbi/1nw32X7Tw_s5T/bibliography/public/

Lab website: https://sites.google.com/rowan.edu/linlab/research

Education:

B.E. (Pharmaceutical Engineering), Zhejiang University, China

PhD (Biochemistry and Biophysical Chemistry), University of Alabama at Birmingham, US

Postdoctoral (Biomedical Science), University of Pennsylvania, US

Research Interests

• AAA+ Protein Mechanisms: Investigating the molecular mechanisms of AAA+ proteins—including Hsp104, p97/VCP, and Thorase/ATAD1, along with their potentiated or disease-associated variants.
• Molecular Chaperones and Disaggregases: Identifying, characterizing, and engineering novel disaggregases, chaperones, and related biomolecules that maintain or restore protein and genome homeostasis. Our work targets aberrant protein aggregation of α-synuclein, transthyretin (TTR), TDP-43, and FUS, which are implicated in Parkinson’s disease (PD), Alzheimer’s disease (AD), AD-related dementias (ADRD), amyloidosis, atherosclerosis, hypertrophic cardiomyopathy (HCM), and amyotrophic lateral sclerosis (ALS).

Mechanistic Focus

1. AAA+ Protein Function: Dissecting conformational dynamics, substrate recognition, and cofactor regulation of Hsp104, p97/VCP, Thorase/ATAD1, and their variants using single-molecule and structural approaches.
2. Discovery and Evolution of Molecular Machines: Identifying and evolving novel disaggregases, chaperones, and related factors that govern proteostasis and genome stability, with emphasis on mechanistic principles and emergent properties.
3. Sequence Grammar of Aggregation-Prone Proteins: Exploring how mutations, isoforms, and post-translational modifications reshape folding landscapes and aggregation kinetics of α-synuclein, transthyretin, TDP-43, and FUS.

Honors and Awards:

• 2024 Postdoctoral Initiatives in Neuroscience Excellence (P-SPINE) Fellow, University of Pennsylvania, PA
• 2024-2025 B&B Research Excellence and Resilience Award, University of Pennsylvania, PA
• 2023-2024 Mildred Cohn Distinguished Postdoctoral Award, University of Pennsylvania, PA
• 2020-2022 Warren Alpert Distinguished Scholar, University of Pennsylvania, PA
• 2018-2021 Alzheimer's Association Research Fellowship, University of Pennsylvania, PA
• 2016 The ADDF Young Investigator Scholarship, University of Pennsylvania, PA
• 2005 Best Thesis winner of the Pharmaceutical Engineering major, Zhejiang University, China
• 2005 Me Sha Dong (Merck China) scholarship, Zhejiang University, China
• 2005 GuangHua scholarship, Zhejiang University, China--
• 2004 Excellent student scholarship, Zhejiang University, China
• 2001–2005 Excellent Student cadre of the College, Zhejiang University, China

Publications:

1. Lin, J., Carman, P.J., Gambogi, C.W., Kendsersky, N.M., Chuang, E., Gates, S.N., Yokom, A.L., Rizo, A.N., Southworth, D.R., and Shorter, J. (2024). "Design principles to tailor Hsp104 therapeutics." Cell Rep 43(12): 115005. PMID: 39671291
2. Tariq, A.*, Lin, J.*,M. Noll*, M.P. Torrente, K.L. Mack, O. Hernandez Murillo, M.E. Jackrel, and J. Shorter. (2018). Potentiating Hsp104 activity via phosphomimetic mutations in the middle domain. FEMS Yeast Res. (*Co-first author). PMCID: PMC6454557.
3. Tariq, A.*, Lin, J.*,E. Jackrel*, C.D. Hesketh, P.J. Carman, K.L. Mack, R. Weitzman, C. Gambogi, O.A. Hernandez Murillo, E.A. Sweeny, E. Gurpinar, A.L. Yokom, S.N. Gates, K. Yee, S. Sudesh, J. Stillman, A.N. Rizo, D.R. Southworth, and J. Shorter. (2019). Mining disaggregase sequence space to safely counter TDP-43, F.U.S., and alpha-synuclein proteotoxicity. Cell Rep. 28(8):2080–2095. (*Co-first author). PMCID: PMC6750954.
4. Lin, J. and Lucius, A.L. (2016). Examination of ClpB Quaternary Structure and Linkage to Nucleotide Binding. Biochemistry 55, 1758-1771. PMID: 26891079.
5. Lin, J. and Lucius, A.L. (2015). Analysis of Linked Equilibria. Methods in Enzymology 562, 161-186. PMID: 26412651.

Review articles (peer-reviewed):

9. Lin, J. ^, Shorter, J^, and Lucius, A.L.^. (2022). AAA+ proteins: one motor, multiple ways to work. Biochem. Soc. Trans. 50(2):895-906. PMCID: PMC9115847
10. Lin, J. and Lucius, A.L. (2015) Examination of the Dynamic Assembly Equilibrium for E. coli ClpB, Proteins 83, 2008-2024. PMID: 23773038

Contributing author articles (peer-reviewed):

11. The Atomwise Aims Program. (2024). AI is a viable alternative to high throughput screening: a 318-target study. Sci. Rep. 14, 7526. PMCID: PMC10987645
12. Mack, K.L.*, H. Kim*, E.M. Barbieri, Lin, J., S. Braganza, M.E. Jackrel, J.E. DeNizio, X. Yan, E. Chuang, A. Tariq, R.R. Cupo, L.M. Castellano, K.A. Caldwell, G.A. Caldwell^, and J. Shorter^. (2023). Tuning Hsp104 specificity to selectively detoxify α-synuclein. Mol. Cell. 83(18):3314-3332.e9. (*Co-first author. ^Co-corresponding author). PMCID: PMC10530207
13. Huang, L., T. Agrawal, G. Zhu, S. Yu, L. Tao, Lin, J., R. Marmorstein, J. Shorter, and X. Yang. (2021). DAXX represents a new type of protein-folding enabler. Nature. 597(7874):132-37. PMCID: PMC8485697
14. March, Z.M., K. Sweeney*, H. Kim*, X. Yan*, L.M. Castellano, M.E. Jackrel, Lin, J., E. Chuang, E. Gomes, C. W. Willicott, K. Michalska, R. Jedrzejczak, A. Joachimiak, K.A. Caldwell, G.A. Caldwell, O. Shalem, and J. Shorter. (2020). Therapeutic genetic variation revealed in diverse Hsp104 homologs. eLife. 9:e57457. (*Co-second author). PMCID: PMC7785292
15. Jones, R.D., C. Enam, R. Ibarra, H.R. Borror, K.E. Mostoller, E.K. Fredrickson, Lin, J., E. Chuang, Z. March, J. Shorter, T. Ravid, G. Kleiger, and R.G. Gardner. (2020). The extent of Ssa1/Ssa2 Hsp70 chaperone involvement in nuclear protein quality control degradation varies with the substrate. Mol. Biol. Cell. 31(3):221-233. PMCID: PMC7001477
16. Lopez, K.E.*, A.N. Rizo*, E. Tse, Lin, J., N.W. Skull, A.C. Thwin, A.L. Lucius, J. Shorter, and D.R. Southworth. (2020). Conformational plasticity of the ClpAP AAA+ protease couples protein unfolding and proteolysis. Nat. Struct. Mol. Biol. (*Co-first author) PMCID: PMC7529148
17. Ye, X., Lin, J., L. Mayne, J. Shorter, and S.W. Englander. (2020). Structural and kinetic basis for the regulation and potentiation of Hsp104 function. Proc. Natl. Acad. Sci. U.S.A. PMCID: PMC7196772
18. Rizo, A.N., Lin, J.,N. Gates, E. Tse, S.M. Bart, L.M. Castellano, F. DiMaio, J. Shorter, and D.R. Southworth. (2019). Structural basis for substrate gripping and translocation by the ClpB AAA+ disaggregase. Nat. Comm. 10:2393. PMCID: PMC6546751
19. Durie, C.L., Lin, J.,W. Scull, K.L. Mack, M.E. Jackrel, E.A. Sweeny, L.M. Castellano, J. Shorter, and A.L. Lucius. (2019). Hsp104 and potentiated variants can operate as distinct non-processive translocases. Biophys. J. 116(10):1856-1872 PMCID: PMC6531783
20. Ye, X., Lin, J., Mayne, J. Shorter, and S.W. Englander. (2019). Hydrogen exchange reveals Hsp104 architecture, structural dynamics, and energetics in physiological solution. Proc. Natl. Acad. Sci. U.S.A. 116(15):7333-7342. PMCID: PMC6462101
21. Gates, S. N.*; Yokom, A. L.*; Lin, J.; Jackrel, M. E.; Rizo, A. N.; Kendsersky, N. M.; Buell, C. E.; Sweeny, E. A.; Mack, K. L.; Chuang, E.; Torrente, M. P.; Su, M.; Shorter, J.; Southworth, D. R., (2017) Ratchet-like polypeptide translocation mechanism of the AAA+ disaggregase Hsp104. Science, 357 (6348), 273-279. (* co-first authors) PMCID: PMC5770238
22. Weaver, C. L., Duran, E. C., Mack, K. L., Lin, J., Jackrel, M. E., Sweeny, E. A., Shorter, J., and Lucius, A. L. (2017) Avidity for Polypeptide Binding by Nucleotide-Bound Hsp104 Structures, PMCID: PMC5649362
23. Li, T., Weaver, C. L., Lin, J., Duran, E. C., Miller, J. M., and Lucius, A. L. (2015) Escherichia coli ClpB is a Non-processive Polypeptide Translocase, The Biochemical Journal 470, 39-52. PMID: 26251445
24. Li, T., Lin, J., and Lucius, A. L. (2015) Examination of polypeptide substrate specificity for Escherichia coli ClpB, Proteins 83, 117-134. PMID: 25363713
25. Fancy, R. M., Wang, L., Napier, T., Lin, J., Jing, G., Lucius, A. L., McDonald, J. M., Zhou, T., and Song, Y. (2014) Characterization of calmodulin-Fas death domain interaction: an integrated experimental and computational study, Biochemistry 53, 2680-2688. PMID: 24702583
26. Miller, J.M., Lin, J., Li, T. and Lucius, A.L. (2013) coli ClpA Catalyzed Polypeptide Translocation is Allosterically Controlled by the Protease ClpP. J. Mol Biol., 425, 2795-2812. PMID: 23639359