Thrombosis, Hemostasis and Vascular Biology

The overall interest of our lab is the mechanism of receptor transmembrane signaling. We focus on cell surface receptors with single transmembrane domains, such as integrins, receptor tyrosine kinases, and receptor-like tyrosine phosphatases. We study how these receptors transmit signals across cell membrane through conformational regulation upon ligand binding at the extracellular domain or stimulations impinging on the cytoplasmic domain. We are using structural biology, biochemistry, and cell biology techniques to illustrate the mechanism of receptor-ligand interactions and conformational changes required for transmembrane signaling at the extracellular, transmembrane and cytoplasmic domains.

Ongoing projects include investigating the conformational requirement for integrin bi-directional transmembrane signaling, structural and functional basis of integrin as pathogen receptors, integrin ligand interaction, and developing antibodies and small molecules targeting or stabilizing specific integrin conformation. Integrins are the important cell surface receptors that regulate cell-cell and cell-matrix interactions in development, hemostasis, antigen recognition, homing and inflammation. Integrin activation is dysregulated under pathological conditions, such as autoimmune disease and thrombosis. Our long-term goal is to understand the correlation of receptor conformational regulation and signal transduction and to help to design more efficient and safe therapeutic agents.

1. Scientist Development Grant, American Heart Association, 2012-2016
2. ASH Scholar Award for Junior Faculty, American Society of Hematology, 2013-2015
3. NHLBI, R56HL122985, 2015-2016
4. NHLBI, R01HL131386, 2016-2020

Former Lab Members:

• Huiying Zhi, Maria Therese Ahlen, Aye Myat Myat Thinn, Hartmut Weiler, Brian R. Curtis, Bjørn Skogen, Jieqing Zhu, and Peter J. Newman. Atomic-level dissection of the polyclonal immune response to the human platelet alloantigen, HPA-1a (PlA1):Implications for diagnosis, prophylaxis and treatment. Blood Advances, 2(21):3001-3011 (2018)
• Aye Myat Myat Thinn, Zhengli Wang, Dongwen Zhou, Yan Zhao, Brian R. Curtis, and Jieqing Zhu. The autonomous conformational regulation of β3 integrin and the conformation-dependent property of HPA-1a alloantibodies. Proc Natl Acad Sci USA, 115(39):E9105-E9114 (2018)   
• Dongwen Zhou, Aye Myat Myat Thinn, Yan Zhao, Zhengli Wang, and Jieqing Zhu. Structure of an extended β3 integrin. Blood, 132(9): 962-972 (2018)
• Aye Myat Myat Thinn, Zhengli Wang, and Jieqing Zhu. The membrane distal regions of integrin α cytoplasmic domains contribute differently to integrin inside-out activation. Scientific Reports, 8(1):5067 (2018)     
• Jieqing Zhu. Csk/CD148 and platelet SFK activation – a balancing act! Blood, 131(10):1042-1043 (2018) 
• Zhengli Wang, Aye Myat Myat Thinn, and Jieqing Zhu. A pivotal role for a conserved bulky residue at the α1-helix of αL integrin I domain in integrin ligand binding. Journal of Biological chemistry, 292(50):20756 (2017)
• Virginie Bondu, Chenyu Wu, Wenpeng Cao, Peter C. Simons, Jennifer Gillette, Jieqing Zhu, Laurie Erb, X. Frank Zhang, and Tione Buranda. Low affinity binding in cis to P2Y2R mediates force-dependent integrin activation during hantavirus infection. Molecular Biology of the Cell, 28(21):2887 (2017)
• Xiulei Cai, Aye Myat Myat Thinn, Zhengli Wang, Hu Shan, and Jieqing Zhu. The importance of N-glycosylation on β3 integrin ligand binding and conformational regulation. Scientific Reports, 7(1):4656 (2017)
• Panida Lertkiatmongkol, Cathy Paddock, Debra K. Newman, Jieqing Zhu, Michael J. Thomas, and Peter J. Newman. The role of sialylated glycans in human PECAM-1-mediated trans-homophilic interactions and endothelial cell barrier function. Journal of Biological chemistry 291(50):26216-26225 (2016)
• Sentot Santoso, Hevi Wihadmadyatami, Tamam Bakchoul, Silke Werth, Nadia Al-Fakhri, Gregor Bein, Volker Kiefel, Jieqing Zhu, Peter J. Newman, Behnaz Bayat, Ulrich J. Sachs. Antiendothelial αvβ3 Antibodies Are a Major Cause of Intracranial Bleeding in Fetal/Neonatal Alloimmune Thrombocytopenia. Arterioscler Thromb Vasc Biol. 36(8):1517-1524 (2016)
• Cathy Paddock, Dongwen Zhou, Panida Lertkiatmongkol, Peter J. Newman, and Jieqing Zhu. Structural basis for PECAM-1 homophilic binding. Blood, 127(8):1052-1061 (2016)
• Jianghai Zhu, Jieqing Zhu, Daniel W. Bougie, Richard H. Aster, and Timothy A. Springer. Structural basis for quinine-dependent antibody binding to platelet integrin. Blood, 126(18):2138-2145 (2015)
• Huiying Zhi, Jing Dai, Junling Liu, Jieqing Zhu, Debra K. Newman, Cunji Gao and Peter J. Newman. Platelet activation and thrombus formation over IgG immune complexes requires integrin αIIbβ3 and Lyn kinase. Plos one, 2015; 10(8):e0135738.
• Jiafu Liu, Zhengli Wang, Aye Myat Myat Thinn, Yan-Qing Ma, and Jieqing Zhu. The dual structural roles of the membrane distal region of α integrin cytoplasmic tail during integrin inside-out activation. Journal of Cell Science 128(9): 1718-1731, (2015).
• Chuanmei Zhang, Jiafu Liu, Xiuli Jiang, Nada Haydar, Can Zhang, Hu Shan, and Jieqing Zhu.  Modulation of integrin activation and signaling by alpha1/alpha1'-helix unbending at the junction. Journal of Cell Science126(24):5735-5747, (2013).
• Jieqing Zhu, Jianghai Zhu, Timothy A. Springer. Complete integrin headpiece opening in eight steps. Journal of Cell Biology 201(7):1053-1068. (2013)
• Yan-Feng Zhou, Edward T. Eng, Jieqing Zhu, Chafen Lu, Thomas Walz, and Timothy A. Springer. Sequence and structure relationships within von Willebrand factor. Blood 120(2):449-58, (2012)
• Daniel W. Bougie, Mark H. Rasmussen, Jieqing Zhu, Richard H. Aster. Antibodies causing thrombocytopenia in patients treated with RGD-mimetic platelet inhibitors recognize ligand-specific conformers of αIIbβ3 integrin. Blood 119(26):6317-25 (2012)
• Jieqing Zhu, Won-Seok Choi, Joshua McCoy, Ana Negri, Jianghai Zhu, Sarasija Naini, Jihong Li, Min Shen, Wenwei Huang, Daniel W. Bougie, Mark Rasmussen, Richard H. Aster, Craig Thomas, Marta Filizola, Timothy A. Springer, Barry S. Coller. Structure-guided design of a high affinity platelet integrin αIIbβ3 receptor antagonist that disrupts Mg2+ binding to the MIDAS. Science Translational Medicine, 4(125): 124ra32 (2012) (Cover story)
•  Wei Wang, Jieqing Zhu, Timothy A. Springer and Bing-Hao Luo. Tests of integrin transmembrane domain homo-oligomerization during integrin ligand binding and signaling. Journal of Biological chemistry 286(3):1860-1867, (2011)
• Chafen Lu, Lizhi Mi, Michael J. Grey, Jieqing Zhu, Elizabeth Graef, Shigeyuki Yokoyama, and Timothy A. Springer. Structural evidence for loose linkage between ligand binding and kinase activation in the epidermal growth factor receptor. Molecular and Cellular Biology 30: 5432-5443, (2010)
• Jieqing Zhu, Jianghai Zhu, Ana Negri, Davide Provasi, Marta Filizola, Barry S. Coller, and Timothy A. Springer. The closed headpiece of integrin αIIbβ3, and its complex with an aIIb-specific antagonist that does not induce opening. Blood 116(23): 5050-5059, (2010)
• Jieqing Zhu, Bing-Hao Luo, Patrick Barth, Jack Schonbrun, David Baker, and Timothy A. Springer. The structure of a receptor with two associating transmembrane domains on the cell surface: integrin αIIbβ3. Molecular Cell 34: 234-249, (2009)
• Jieqing Zhu, Christopher V. Carman, Minsoon Kim, Motomu Shimaoka, Timothy A. Springer, and Bing-Hao Luo. Requirement of α and β subunit transmembrane helix separation for integrin outside-in signaling. Blood 110(7): 2475-2483, (2007)
• Jieqing Zhu, Brian Boylan, Bing-Hao Luo, Peter J. Newman, and Timothy A. Springer. Tests of the extension and deadbolt models of integrin activation. Journal of Biological chemistry 282(16): 11914-11920, (2007)
• Yueyong Liu, Yanhui Xu, Zhiyong Lou, Jieqing Zhu, Xuebo Hu, George F Gao, Bingsheng Qiu, Zihe Rao, and Po Tien.  Structure characterization of Mumps virus fusion protein core.  Biochem. Biophys. Red. Commun. 348(3):916-922 (2006)
• Jieqing Zhu, Xiuli Jiang, Yueyong Liu, Po Tien, and George F. Gao. Design and characterization of viral polypeptide inhibitors targeting Newcastle disease virus fusion. Journal of Molecular Biology 354: 601-613, (2005)
• Yueyong Liu , Yanhui Xu , Jieqing Zhu , Bingsheng Qiu , Zihe Rao , George F. Gao, and Po Tien. Crystallization and preliminary X-ray diffraction analysis of central structure domains from mumps virus F protein. Acta Crystallographica Section F 61(9): 855-857, (2005)
• Ling Ni, Jieqing Zhu, Junjie Zhang, Meng Yan, George F. Gao, and Po Tien. Design of recombinant protein-based SARS-CoV entry inhibitors targeting the heptad-repeat regions of the spike protein S2 domain. Biochem. Biophys. Res. Commun. 330(1): 39-45, (2005)
• Yueyong Liu, Jieqing Zhu, Mingguang, Feng, Po Tien, and George F. Gao. Six-helix bundle assembly and analysis of the central core of mumps virus fusion protein. Archives of Biochemistry and Biophysics. 421(1): 143-148, (2004)
• Jieqing Zhu, Gengfu Xiao, Yanhui Xu, Fang Yuan, Congyi Zheng, Yueyong Liu, Huimin Yan, David K. Cole, John I. Bell, Zihe Rao, Po Tien, and George F. Gao. Following the rule: formation of the 6-helix bundle of the fusion core from severe acute respiratory syndrome coronavirus spike protein and identification of potent peptide inhibitors. Biochem. Biophys. Res. Commun. 319(1): 283-288, (2004)
• Yanhui Xu, Jieqing Zhu, Yiwei Liu, Zhiyong Lou, Fang Yuan, Yueyong Liu, David K. Cole, Ling Ni, Nan Su, Lan Qin, Xu Li, Zhihong Bai, John I. Bell, Hai Pang, Po Tien, George F. Gao, and Zihe Rao. Characterization of heptad repeat regions, HR1 and HR2, and design of a fusion core structure model of the spike protein from severe acute respiratory syndrome (SARS) coronavirus. Biochemistry. 43(44): 14064-14071, (2004)
• Jieqing Zhu, Yi Ding, Feng Gao, Tinghe Wu, Catherine W.-H. Zhang, Po Tien, Zihe Rao, and George F. Gao. Crystallization and preliminary crystallographic analysis of the trimer core from Measles virus fusion protein. Acta Crystallogr D Biol Crystallogr. 59:587-590, (2003)
• Jieqing Zhu, Pengyun Li, Tinghe Wu, Feng Gao, Yi Ding, Catherine W.-H. Zhang, Zihe Rao, George F. Gao, and Po Tien. Design and analysis of post-fusion 6-helix bundle construct of heptad repeat regions from Newcastle disease virus F protein. Protein Engineering 16(5): 373-379, (2003)
• Jieqing Zhu, Catherine W.-H. Zhang, Zihe Rao, Po Tien, and George F. Gao. Biochemical and biophysical analysis of heptad repeat regions from the fusion protein of Menangle virus, a newly emergent paramyxovirus. Archives of Virology 148(7): 1301-1316, (2003)
• Pengyun Li, Jieqing Zhu, Beili Wu, Feng Gao, Po Tien, Zihe Rao, and George F. Gao. Crystallization and preliminary crystallographic analysis of post-fusion 6-helix bundle core structure from Newcastle disease virus F protein. Acta Crystallogr D Biol Crystallogr. 59: 1296-1298, (2003)
• Jieqing Zhu, Catherine W.-H. Zhang, Yipeng Qi, Po Tien, and George F. Gao. The fusion protein core of measles virus forms stable coiled coil trimer. Biochem. Biophys. Res. Commun. 299: 897-902, (2002)