| Structural highlights
Function
HPSE_HUMAN Endoglycosidase that cleaves heparan sulfate proteoglycans (HSPGs) into heparan sulfate side chains and core proteoglycans. Participates in extracellular matrix (ECM) degradation and remodeling. Selectively cleaves the linkage between a glucuronic acid unit and an N-sulfo glucosamine unit carrying either a 3-O-sulfo or a 6-O-sulfo group. Can also cleave the linkage between a glucuronic acid unit and an N-sulfo glucosamine unit carrying a 2-O-sulfo group, but not linkages between a glucuronic acid unit and a 2-O-sulfated iduronic acid moiety. It is essentially inactive at neutral pH but becomes active under acidic conditions such as during tumor invasion and in inflammatory processes. Facilitates cell migration associated with metastasis, wound healing and inflammation. Enhances shedding of syndecans, and increases endothelial invasion and angiogenesis in myelomas. Acts as procoagulant by increasing the generation of activation factor X in the presence of tissue factor and activation factor VII. Increases cell adhesion to the extacellular matrix (ECM), independent of its enzymatic activity. Induces AKT1/PKB phosphorylation via lipid rafts increasing cell mobility and invasion. Heparin increases this AKT1/PKB activation. Regulates osteogenesis. Enhances angiogenesis through up-regulation of SRC-mediated activation of VEGF. Implicated in hair follicle inner root sheath differentiation and hair homeostasis.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12]
Publication Abstract from PubMed
Heparanase is the only human enzyme known to hydrolyse heparin sulfate and is involved in many important physiological processes. However, it is also unregulated in many disease states, such as cancer, diabetes and Covid-19. It is thus an important drug target, yet the heterologous production of heparanase is challenging and only possible in mammalian or insect expression systems, which limits the ability of many laboratories to study it. Here we describe the computational redesign of heparanase to allow high yield expression in Escherchia coli. This mutated form of heparanase exhibits essentially identical kinetics, inhibition, structure and protein dynamics to the wild type protein, despite the presence of 26 mutations. This variant will facilitate wider study of this important enzyme and contributes to a growing body of literature that shows evolutionarily conserved and functionally neutral mutations can have significant effects on protein folding and expression.
Computational design and experimental characterisation of a stable human heparanase variant.,Whitefield C, Hong N, Mitchell JA, Jackson CJ RSC Chem Biol. 2022 Feb 15;3(3):341-349. doi: 10.1039/d1cb00239b. eCollection , 2022 Mar 9. PMID:35382258[13]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Okada Y, Yamada S, Toyoshima M, Dong J, Nakajima M, Sugahara K. Structural recognition by recombinant human heparanase that plays critical roles in tumor metastasis. Hierarchical sulfate groups with different effects and the essential target disulfated trisaccharide sequence. J Biol Chem. 2002 Nov 8;277(45):42488-95. Epub 2002 Sep 3. PMID:12213822 doi:http://dx.doi.org/10.1074/jbc.M206510200
- ↑ Goldshmidt O, Zcharia E, Cohen M, Aingorn H, Cohen I, Nadav L, Katz BZ, Geiger B, Vlodavsky I. Heparanase mediates cell adhesion independent of its enzymatic activity. FASEB J. 2003 Jun;17(9):1015-25. PMID:12773484 doi:http://dx.doi.org/10.1096/fj.02-0773com
- ↑ Gingis-Velitski S, Zetser A, Flugelman MY, Vlodavsky I, Ilan N. Heparanase induces endothelial cell migration via protein kinase B/Akt activation. J Biol Chem. 2004 May 28;279(22):23536-41. Epub 2004 Mar 24. PMID:15044433 doi:http://dx.doi.org/10.1074/jbc.M400554200
- ↑ Zetser A, Bashenko Y, Edovitsky E, Levy-Adam F, Vlodavsky I, Ilan N. Heparanase induces vascular endothelial growth factor expression: correlation with p38 phosphorylation levels and Src activation. Cancer Res. 2006 Feb 1;66(3):1455-63. PMID:16452201 doi:http://dx.doi.org/10.1158/0008-5472.CAN-05-1811
- ↑ Malgouries S, Donovan M, Thibaut S, Bernard BA. Heparanase 1: a key participant of inner root sheath differentiation program and hair follicle homeostasis. Exp Dermatol. 2008 Dec;17(12):1017-23. doi: 10.1111/j.1600-0625.2008.00739.x., Epub 2008 Jun 14. PMID:18557927 doi:http://dx.doi.org/10.1111/j.1600-0625.2008.00739.x
- ↑ Cohen-Kaplan V, Naroditsky I, Zetser A, Ilan N, Vlodavsky I, Doweck I. Heparanase induces VEGF C and facilitates tumor lymphangiogenesis. Int J Cancer. 2008 Dec 1;123(11):2566-73. doi: 10.1002/ijc.23898. PMID:18798279 doi:http://dx.doi.org/10.1002/ijc.23898
- ↑ Fux L, Feibish N, Cohen-Kaplan V, Gingis-Velitski S, Feld S, Geffen C, Vlodavsky I, Ilan N. Structure-function approach identifies a COOH-terminal domain that mediates heparanase signaling. Cancer Res. 2009 Mar 1;69(5):1758-67. doi: 10.1158/0008-5472.CAN-08-1837. Epub, 2009 Feb 24. PMID:19244131 doi:http://dx.doi.org/10.1158/0008-5472.CAN-08-1837
- ↑ Purushothaman A, Uyama T, Kobayashi F, Yamada S, Sugahara K, Rapraeger AC, Sanderson RD. Heparanase-enhanced shedding of syndecan-1 by myeloma cells promotes endothelial invasion and angiogenesis. Blood. 2010 Mar 25;115(12):2449-57. doi: 10.1182/blood-2009-07-234757. Epub 2010 , Jan 22. PMID:20097882 doi:http://dx.doi.org/10.1182/blood-2009-07-234757
- ↑ Peterson SB, Liu J. Unraveling the specificity of heparanase utilizing synthetic substrates. J Biol Chem. 2010 May 7;285(19):14504-13. doi: 10.1074/jbc.M110.104166. Epub 2010, Feb 24. PMID:20181948 doi:http://dx.doi.org/10.1074/jbc.M110.104166
- ↑ Smith PN, Freeman C, Yu D, Chen M, Gatenby PA, Parish CR, Li RW. Heparanase in primary human osteoblasts. J Orthop Res. 2010 Oct;28(10):1315-22. doi: 10.1002/jor.21138. PMID:20309870 doi:http://dx.doi.org/10.1002/jor.21138
- ↑ Poon IK, Yee DY, Jones AL, Wood RJ, Davis DS, Freeman C, Parish CR, Hulett MD. Histidine-rich glycoprotein binds heparanase and regulates its enzymatic activity and cell surface interactions. Int J Biochem Cell Biol. 2010 Sep;42(9):1507-16. doi:, 10.1016/j.biocel.2010.05.008. Epub 2010 May 31. PMID:20561914 doi:http://dx.doi.org/10.1016/j.biocel.2010.05.008
- ↑ Ramani VC, Yang Y, Ren Y, Nan L, Sanderson RD. Heparanase plays a dual role in driving hepatocyte growth factor (HGF) signaling by enhancing HGF expression and activity. J Biol Chem. 2011 Feb 25;286(8):6490-9. doi: 10.1074/jbc.M110.183277. Epub 2010, Dec 3. PMID:21131364 doi:http://dx.doi.org/10.1074/jbc.M110.183277
- ↑ Whitefield C, Hong N, Mitchell JA, Jackson CJ. Computational design and experimental characterisation of a stable human heparanase variant. RSC Chem Biol. 2022 Feb 15;3(3):341-349. PMID:35382258 doi:10.1039/d1cb00239b
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