X. Long Zheng
Assistant Professor, Pathology and Laboratory Medicine

Cell Biology and Physiology Program

Address

Abramson Research Building 816G
34th St and Civic Center Blvd
Philadelphia, PA 19104

Office tel.: 215 590-3565
Lab tel.: 215 590-3890
Fax: 215 590-4834
E-mail: zheng@email.chop.edu

Nanchang University School of Medicine, China: MD (Medicine), 1984.

University of Vienna, Austria: PhD (Mol. & Cell Biology).

Washington University, St. Louis, MO: Residency and fellowship (Clinical Pathology).

Research Interests

• Biosynthesis and Structure-Function of ADAMTS13 Metalloprotease.

Key words: Von Willebrand factor, Protease, Thrombotic Thrombocytopenic Purpura.

Description of Research

ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats) is a reprolysin-like metalloprotease that limits platelet aggregation by cleavage of the Tyr1605-Met1606 bond at the central A2 subunit of von Willebrand factor (VWF). Deficiency of ADAMTS13 results in an accumulation of “unusually large” VWF multimers that are released from endothelial cells, leading to spontaneous platelet aggregation and subsequent thrombosis in small arteries, exhibiting a thrombotic thrombocytopenic purpura (TTP) syndrome. We have determined the domain structure of ADAMTS13, which consists of a propeptide, a metalloprotease domain, a disintegrin domain and first thrombospondin type 1 repeat (TSP1), followed by a Cys-rich domain and a spacer domain. The carboxyl terminus of ADAMTS13 has additional seven TSP1 repeats and two CUB domains. However, the domains of ADAMTS13 required for substrate recognition and specificity are not known. Neither are the exact type of cells that synthesizes ADAMTS13 in the liver and the structural determinants that direct intracellular sorting or secretion of ADAMTS13 characterized.

We are investigating:

1. the ADAMTS13 domains required for substrate recognition and specificity;
2. the cellular origin of ADAMTS13 biosynthesis;
3. the polarity of ADAMTS13 secretion in epithelial and endothelial cells;
4. the signals and mechanisms that direct ADAMTS13 sorting;
5. the effect of ADAMTS13 mutations in patients with congenital TTP on ADAMTS13 sorting or secretion and ADAMTS13-VWF interaction. Recombinant DNA, protein engineering, expression and purification, cell culture, immunofluorescent and confocal microscopy, and various other biochemical and biophysical assays (i.e. surface plasmon resonance) will be employed in the laboratory. The advancement in this area will not only provide more insight into pathogenesis of TTP, but also provide better tools for diagnosis and cure of TTP, as well as other thrombotic disorders.
   

Selected Publications

Zheng X, Chung D, Takayama TK, Majerus EM, Sadler JE, Fujikawa K. (2001). Structure of von Willebrand factor-cleaving protease (ADAMTS13), a metalloprotease involved in thrombotic thrombocytopenic purpura. J Biol. Chem. 276 (44): 41059-63.

Zheng XL, Nishio K, Majerus EM, Sadler JE. (2003). Cleavage of von Willebrand factor requires the spacer domain of the metalloprotease ADAMTS13. J. Biol. Chem. 278 (32): 30136-30141

Zheng XL, Kaufman RM, Goodnough LT, Sadler JE. (2004). Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and non-idiopathic thrombotic thrombocytopenic purpura. Blood 103 (11): 4043-4049.

Ai J, Smith P, Wang S, Zhang P, Zheng XL. (2005). The proximal carboxyl-terminal domains of ADAMTS13 determine substrate specificity and are all required for cleavage of von Willebrand factor. J Biol. Chem. 19; 280 (33): 29428-34.

Shang D, Zheng XW, Niiya M, Zheng XL (2006). Apical sorting of ADAMTS13 in vascular endothelial cells and Madin-Darby canine kidney cells depends on the CUB domains and their association with lipid rafts. Blood 108 (7): 2209-2217.

Search PubMed for more articles

Lab

1. Structure-function relationship of ADAMTS13 in vitro and in vivo
2. Biosynthesis and processing of von Willebrand factor by ADAMTS13 on endothelial cells.
3. Cofactor-dependent regulation of ADAMTS13 function
4. Gene therapy for ADAMTS13 deficiency in a murine model.

Lab Personnel:

Dr. Shang, David, Postdoctoral fellow
Dr. Jin, Shengyu, Postdoctoral fellow
Dr. Cao, Wendy, Postdoctoral fellow
Skipwith, Christopher G. , PhD student
Jno-Charles, Odella , Undergraduate
Miranda, Carolina, Undergraduate
Le, Marilyn, Undergraduate