Education:
- PhD, University of Tennessee, 1994
Clinical/Research Interests:
Bcl-2 family proteins regulated cell death and its relationship to development and treatment of cancer; Biosynthesis and functional structure of membrane proteins.
Programmed cell death (apoptosis) plays an essential role in embryogenesis and adult tissue homeostasis of multicellular organisms by removing unwanted and damaged cells. Impaired regulation of apoptosis is implicated in diseases from cancer to autoimmune disorder to degenerative syndrome. In fact evading apoptosis has been identified as the first of the six critical steps toward carcinogenesis. Two kinds of signals can trigger apoptosis, the death signals received by death receptors on cell surface and the stress signals such as depletion of growth factor and genotypic damages. These apoptotic signals provoke the activation of a set of proteases and nucleases that cleave critical proteins and DNAs to dismantle the cell. Various apoptotic stimuli route through mitochondria to signal the death device. Not surprisingly the decision to launch death program relies primarily on those Bcl-2 family proteins that sooner or later use the mitochondria as their battle field.
The Bcl-2 family includes anti-apoptotic Bcl-2, pro-apoptotic Bax and pro-apoptotic BH3 proteins. These proteins share sequence homology in at least one of the four Bcl-2 homology (BH) motifs. Various stress/death signals activate BH3 proteins. This enhances the interactions of BH3 proteins with the mitochondria and other Bcl-2 family proteins. A few active BH3 proteins can directly activate Bax proteins. Active Bax proteins change conformation, insert into the mitochondrial membrane and form oligomers. The Bax oligomers permeabilize the mitochondrial membrane, releasing pro-death proteins that activate caspases and nucleases and triggering apoptosis. Bcl-2 proteins bind active Bax proteins, preventing them from oligomerization in and permeabilization of the mitochondrial membrane. Many BH3 proteins can bind the Bcl-2 proteins, preventing them from interacting and inhibiting Bax proteins. The interactions among Bcl-2 family proteins are thus complex. Which interaction(s) plays a dominant role in the decision-making process during apoptosis induction has always been a hotly debated issue since the discovery of Bcl-2 family.
My group is currently addressing the following important questions about the structure and function of Bcl-2 family proteins. How Bcl-2 protects cells, and how BH3 and Bax kill cells? How Bcl-2 inhibits Bax, and how BH3 inhibits Bcl-2? What is the structure of these proteins in healthy or dying cells? What is the structure of these proteins told us about their function during cell death? Can we use the structural information to design drugs that will alter the function of these proteins? Will these drugs be effective in kill cancer cells? We are using a combination of biochemical, biophysical, cell biological and molecular approaches to answer these questions in model systems related to various cancers. We are also interested in setting up collaborations to study Bcl-2 family proteins in other disease-related model systems.
Select Publications:
Lv, F.+, Qi, F.*+, Zhang, Z.*+, Wen, M.+, Kale, J., Piai, A., Du, L., Zhou, L., Yang, Y., Wu, B., Liu, Z., del Rosario, J.*, Pogmore, J., Chou, J.J., Andrews, D.W.#, Lin, J.#, OuYang, B.# (2021). An amphipathic Bax core dimer forms part of the apoptotic pore wall in the mitochondrial membrane. EMBO Journal, 40(14), e106438. DOI: 10.1101/2020.12.18.423546
Zhang, Z.*, Huang, B., Zhang, X. C., Lin, J.# (2021). Cysteine-based crosslinking approach for characterization of oligomeric pore-forming proteins in the mitochondrial membranes. Methods in Enzymology, 649, 371-396. DOI: 10.1016/bs.mie.2021.01.023
Wen, M., Cao, Y., Wu, B., Xiao, T., Cao, R., Wang, Q., Liu, X., Xue, H., Yu, Y., Lin, J., Xu, C., Xu, J., and OuYang, B.# (2021). PD-L1 degradation is regulated by electrostatic membrane association of its cytoplasmic domain. Nature Communication, 12(1), 5106. DOI: 10.1038/s41467-021-25416-7
Chi, X., Nguyen, D., Pemberton, J. M., Osterlund, E. J., Liu, Q., Brahmbhatt, H., Zhang, Z.*, Lin, J., Leber, B., Andrews, D. W.# (2020). The carboxyl-terminal sequence of bim enables bax activation and killing of unprimed cells. eLife, 9. PMID: 31976859. DOI: 10.7554/eLife.44525
Ma K, Zhang Z, Chang R, Cheng H, Mu C, Zhao T, Chen L, Zhang C, Luo Q, Lin J, Zhu Y, Chen Q. Dynamic PGAM5 Multimers Dephosphorylate BCL-xL or FUNDC1 to Regulate Mitochondrial and Cellular Fate. Cell Death and Differentiation. 2019 Jul 31. PMID: 31367011. [Epub ahead of print]
Niu X, Brahmbhatt H, Mergenthaler P, Zhang Z, Sang J, Daude M, Ehlert FGR,
Diederich WE, Wong E, Zhu W, Pogmore J, Nandy JP, Satyanarayana M, Jimmidi RK, Arya P, Leber B, Lin J, Culmsee C, Yi J, Andrews DW. A Small-Molecule Inhibitor of Bax and Bak Oligomerization Prevents Genotoxic Cell Death and Promotes Neuroprotection. Cell chemical biology. 2017; 24(4):493-506.e5. PubMed [journal] PMID: 28392146
Liao C, Zhang Z, Kale J, Andrews DW, Lin J, Li J. Conformational Heterogeneity of Bax Helix 9 Dimer for Apoptotic Pore Formation. Scientific reports. 2016; 6:29502. PubMed [journal] PMID: 27381287, PMCID: PMC4933972
Zhang Z, Subramaniam S, Kale J, Liao C, Huang B, Brahmbhatt H, Condon SG, Lapolla SM, Hays FA, Ding J, He F, Zhang XC, Li J, Senes A, Andrews DW, Lin J. BH3-in-groove dimerization initiates and helix 9 dimerization expands Bax pore assembly in membranes. The EMBO journal. 2016; 35(2):208-36. PubMed [journal] PMID: 26702098, PMCID: PMC4718459
Ding J, Mooers BH, Zhang Z, Kale J, Falcone D, McNichol J, Huang B, Zhang XC, Xing C, Andrews DW, Lin J. After embedding in membranes antiapoptotic Bcl-XL protein binds both Bcl-2 homology region 3 and helix 1 of proapoptotic Bax protein to inhibit apoptotic mitochondrial permeabilization. The Journal of biological chemistry. 2014; 289(17):11873-96. PubMed [journal] PMID: 24616095, PMCID: PMC4002096
Medina AP, Lin J, Weigel PH. Hyaluronan synthase mediates dye translocation across liposomal membranes. BMC biochemistry. 2012; 13:2. PubMed [journal] PMID: 22276637, PMCID: PMC3331846
Zhao L, He F, Liu H, Zhu Y, Tian W, Gao P, He H, Yue W, Lei X, Ni B, Wang X, Jin H, Hao X, Lin J, Chen Q. Natural diterpenoid compound elevates expression of Bim protein, which interacts with antiapoptotic protein Bcl-2, converting it to proapoptotic Bax-like molecule. The Journal of biological chemistry. 2012; 287(2):1054-65. PubMed [journal] PMID: 22065578, PMCID: PMC3256916
Ko JK, Choi KH, Peng J, He F, Zhang Z, Weisleder N, Lin J, Ma J. Amphipathic
tail-anchoring peptide and Bcl-2 homology domain-3 (BH3) peptides from Bcl-2 family proteins induce apoptosis through different mechanisms. The Journal of biological chemistry. 2011; 286(11):9038-48. PubMed [journal] PMID: 21189256, PMCID: PMC3059050
Leber B, Lin J, Andrews DW. Still embedded together binding to membranes
regulates Bcl-2 protein interactions. Oncogene. 2010; 29(38):5221-30. PubMed [journal] PMID: 20639903
Ding J, Zhang Z, Roberts GJ, Falcone M, Miao Y, Shao Y, Zhang XC, Andrews DW, Lin J. Bcl-2 and Bax interact via the BH1-3 groove-BH3 motif interface and a novel interface involving the BH4 motif. The Journal of biological chemistry. 2010; 285(37):28749-63. PubMed [journal] PMID: 20584903, PMCID: PMC2937903
Zhang Z, Zhu W, Lapolla SM, Miao Y, Shao Y, Falcone M, Boreham D, McFarlane N, Ding J, Johnson AE, Zhang XC, Andrews DW, Lin J. Bax forms an oligomer via separate, yet interdependent, surfaces. The Journal of biological chemistry. 2010; 285(23):17614-27. PubMed [journal] PMID: 20382739, PMCID: PMC2878526
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