Activation Route of the Schistosoma mansoni Cathepsin B1 Drug Target: Structural Map with a Glycosaminoglycan Switch

0438380 - ÚOCHB 2015 RIV GB eng J - Journal Article
Jílková, Adéla - Horn, Martin - Řezáčová, Pavlína - Marešová, Lucie - Fajtová, Pavla - Brynda, Jiří - Vondrášek, Jiří - McKerrow, J. H. - Caffrey, C. R. - Mareš, Michael
Activation Route of the Schistosoma mansoni Cathepsin B1 Drug Target: Structural Map with a Glycosaminoglycan Switch.
Structure. Roč. 22, č. 12 (2014), s. 1786-1798. ISSN 0969-2126. E-ISSN 1878-4186
R&D Projects: GA ČR GA203/09/1585; GA MŠMT LH12023; GA MŠMT LO1302
Institutional support: RVO:61388963 ; RVO:68378050
Keywords : human procathepsin B * slow binding inhibition * asparaginyl endopeptidase
Subject RIV: CE - Biochemistry
Impact factor: 5.618, year: 2014

Cathepsin B1 (SmCB1) is a digestive protease of the parasitic blood fluke Schistosoma mansoni and a drug target for the treatment of schistosomiasis, a disease that afflicts over 200 million people. SmCB1 is synthesized as an inactive zymogen in which the N-terminal propeptide blocks the active site. We investigated the activation of the zymogen by which the propeptide is proteolytically removed and its regulation by sulfated polysaccharides (SPs). We determined crystal structures of three molecular forms of SmCB1 along the activation pathway: the zymogen, an activation intermediate with a partially cleaved propeptide, and the mature enzyme. We demonstrate that SPs are essential for the autocatalytic activation of SmCB1, as they interact with a specific heparin-binding domain in the propeptide. An alternative activation route is mediated by an S. mansoni asparaginyl endopeptidase (legumain) which is downregulated by SPs, indicating that SPs act as a molecular switch between both activation mechanisms.
Permanent Link: http://hdl.handle.net/11104/0241842