Volume 3 Issue 12
Dec.  2012
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Wei Dong, Weiqin Lu, Wallace L. McKeehan, Yongde Luo, Sheng Ye. Structural basis of heparan sulfate-specific degradation by heparinase Ⅲ[J]. Protein&Cell, 2012, 3(12): 950-961. doi: 10.1007/s13238-012-2056-z
Citation: Wei Dong, Weiqin Lu, Wallace L. McKeehan, Yongde Luo, Sheng Ye. Structural basis of heparan sulfate-specific degradation by heparinase Ⅲ[J]. Protein&Cell, 2012, 3(12): 950-961. doi: 10.1007/s13238-012-2056-z

Structural basis of heparan sulfate-specific degradation by heparinase Ⅲ

doi: 10.1007/s13238-012-2056-z
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We thank Sheng Huang and Jianhua He at Shanghai Synchrotron Radiation Facility (SSRF) for on-site assistance. This work was supported in part by funds from Ministry of Science and Technology (No. 2011CB910500), the National Natural Science Foundation of China (Grant No. 31070661), the Natural Science Foundation of Zhejiang Province (No. R2100439), the Specialized Research Fund for the Doctoral Program of Higher Education (No. 20110101110122), and the Fundamental Research Funds for the Central Universities (SY), US Public Health Service grants (No. DK56338) (Texas Medical Center Digestive Diseases Center) and Texas A&M Health Science Center Enhancement Grant (YL), and CA05997 and P50 CA140388 (WLM). The structure coordinates and reflection files are deposited in the protein data bank under accession number 4FNV.

  • Received Date: 2012-06-05
  • Rev Recd Date: 2012-06-17
  • Heparinase Ⅲ (HepⅢ) is a 73-kDa polysaccharide lyase (PL) that degrades the heparan sulfate (HS) polysaccharides at sulfate-rare regions, which are important co-factors for a vast array of functional distinct proteins including the well-characterized antithrombin and the FGF/FGFR signal transduction system. It functions in cleaving metazoan heparan sulfate (HS) and providing carbon, nitrogen and sulfate sources for host microorganisms. It has long been used to deduce the structure of HS and heparin motifs; however, the structure of its own is unknown. Here we report the crystal structure of the HepⅢ from Bacteroides thetaiotaomicron at a resolution of 1.6 Å. The overall architecture of HepⅢ belongs to the (α/α)5 toroid subclass with an N-terminal toroid-like domain and a C-terminal β-sandwich domain. Analysis of this high-resolution structure allows us to identify a potential HS substrate binding site in a tunnel between the two domains. A tetrasaccharide substrate bound model suggests an elimination mechanism in the HS degradation. Asn260 and His464 neutralize the carboxylic group, whereas Tyr314 serves both as a general base in C-5 proton abstraction, and a general acid in a proton donation to reconstitute the terminal hydroxyl group, respectively. The structure of HepⅢ and the proposed reaction model provide a molecular basis for its potential practical utilization and the mechanism of its eliminative degradation for HS polysaccarides.
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