The Zhang laboratory focuses on the role of the early secretory pathway deficiencies in human diseases. Up to one-third of all cellular proteins traverse the secretory pathway en route to their final intra- or extra-cellular destinations. Many secretory proteins are thought to require cargo receptors for efficient ER-to-Golgi transport. The best known mammalian cargo receptor is the LMAN1-MCFD2 protein complex. Mutations in either genes lead to a bleeding disorder called combined deficiency of factor V and factor VIII.
Using biochemistry, cell biology and mouse models, researches in the Zhang lab characterize the organization of the LMAN1-MCFD2 complex and elucidate how it recognizes and binds properly folded proteins in the ER and selectively releases its cargo in the post-ER compartments. Using knowledge gained, researchers can improve factor VIII secretion in vivo and in vitro that will benefit patients with hemophilia A. Recent evidence suggests additional functions of this cargo receptor complex beyond the transport of clotting factors. Dr. Zhang seeks to understand its role in other biological processes, such as cancer development, and identify additional proteins that are secreted through this pathway.
Proteins that exit the ER are packaged into COPII-coated vesicles. Mammalian cells contain multiple isoforms of the COPII proteins. Recent genetic studies have attributed distinct human disorders to mutations in specific COPII isoforms. The Zhang lab uses mouse models to study the mechanisms of inherited diseases caused by deficiencies of individual COPII isoforms and gain insight into the in vivo functions of these important proteins.
- Zhu M, Tao J, Vasievich MP, Wei W, Zhu G, Khoriaty R, Zhang B. Neurotube opening and abnormal extraembryonic membrane development in SEC23A deficient mice. Sci. Rep. 2015;5:15471.
- Yehia L, Niazi F, Ni Y, Ngeow J, Sankunny M, Liu Z, Wei W, Mester JL, Keri RA, Zhang B, Eng C. Germline heterozygous variants in SEC23B are associated with Cowden syndrome and enriched in apparently sporadic thyroid cancer. Am J Hum Genet. 2015;97:661-76.
- Khoriaty R, Vasievich MP, Jones M, Everett L, Chase J, Tao J, Siemieniak D, Zhang B, Maillard I, Ginsburg D. Absence of a red blood cell phenotype in mice with hematopoietic deficiency of SEC23B. Mol Cell Biol. 2014;34(19):3721-34.
- Zheng C, Page RC, Das V, Nix JC, Wigren E, Misra S, Zhang B. Structural characterization of carbohydrate binding by LMAN1 provides new insight into the endoplasmic reticulum export of FV and FVIII. J Biol Chem. 2013;288:20499-509.
- Patel AJ, Liu H-H, Lager RA, Malkovska V, Zhang B. Successful percutaneous coronary intervention in a patient with combined deficiency of FV and FVIII due to novel compound heterozygous mutations in LMAN1. Haemophilia. 2013;19,607-610.
- Chen X-W, Wang H, Bajaj K, Zhang P, Meng Z, Ma D, Bai Y, Adams E, Baines A, Yu G, Liu H-H, Sartor MA, Zhang B, Yi Z, Lin J, Young SG, Schekman R, Ginsburg D. SEC24A deficiency lowers plasma cholesterol through reduced PCSK9 secretion. eLife. 2013;2:e00444.
- Klaus J, Eisenhauer P, Russo J, Mason A, Do D, Taatjes D, Cornillez-Ty C, Zheng C. Boyson J, Lao L, Zhang B, Ballif B, Botten J. The intracellular cargo receptor ERGIC-53 is required for the production of infectious arenavirus particles. Cell Host Microbe. 2013;14:522–534.
- Tao J, Zhu M, Wang H, Afelik S, Vasievich MP, Chen XW, Zhu G, Jensen J, Ginsburg D, Zhang B. SEC23B is required for the maintenance of murine professional secretory tissues. Proc Natl Acad Sci USA. 2012;109:E2001-9.
- Zhu M, Das V, Zheng C, Majumdar S, Zhang B. A synonymous mutation in LMAN1 creates an ectopic splice donor site and causes combined deficiency of FV and FVIII. J Throm Haemost. 2012;10(11):2407-2409.
- Zhang B, Zheng C, Zhu M, Tao J, Vasievich M, Baines A, Kim J, Schekman R, Kaufman RJ, Ginsburg D. Mice deficient in LMAN1 exhibit FV and FVIII deficiencies and liver accumulation of a1-antitrypsin. Blood. 2011;118:3384-91.
- Zheng C, Liu HH, Yuan S, Zhou J, Zhang B. Molecular basis of LMAN1 in coordinating LMAN1-MCFD2 cargo receptor formation and ER-to-Golgi transport of FV/FVIII. Blood. 2010;116:5698-706.
- Zheng C, Liu HH, Zhou J, Zhang B. EF hand domains of MCFD2 mediate interactions with both LMAN1 and coagulation factor V or VIII. Blood. 2010;115:1081-7.
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