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Statements

Subject Item
n2:RIV%2F00216208%3A11310%2F14%3A10289025%21RIV15-MSM-11310___
rdf:type
n6:Vysledek skos:Concept
rdfs:seeAlso
http://dx.doi.org/10.1016/j.str.2014.09.015
dcterms:description
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. 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.
dcterms:title
Activation Route of the Schistosoma mansoni Cathepsin B1 Drug Target: Structural Map with a Glycosaminoglycan Switch Activation Route of the Schistosoma mansoni Cathepsin B1 Drug Target: Structural Map with a Glycosaminoglycan Switch
skos:prefLabel
Activation Route of the Schistosoma mansoni Cathepsin B1 Drug Target: Structural Map with a Glycosaminoglycan Switch Activation Route of the Schistosoma mansoni Cathepsin B1 Drug Target: Structural Map with a Glycosaminoglycan Switch
skos:notation
RIV/00216208:11310/14:10289025!RIV15-MSM-11310___
n4:aktivita
n14:S n14:P n14:I
n4:aktivity
I, P(GA203/09/1585), P(LH12023), P(LO1302), S
n4:cisloPeriodika
12
n4:dodaniDat
n15:2015
n4:domaciTvurceVysledku
n13:1888986
n4:druhVysledku
n8:J
n4:duvernostUdaju
n16:S
n4:entitaPredkladatele
n11:predkladatel
n4:idSjednocenehoVysledku
1515
n4:idVysledku
RIV/00216208:11310/14:10289025
n4:jazykVysledku
n20:eng
n4:klicovaSlova
expression; chemotherapy; ph; propeptide; cysteine proteases; hemoglobin digestion; in-vitro; asparaginyl endopeptidase; slow-binding inhibition; human procathepsin-b
n4:klicoveSlovo
n7:chemotherapy n7:asparaginyl%20endopeptidase n7:slow-binding%20inhibition n7:in-vitro n7:cysteine%20proteases n7:expression n7:human%20procathepsin-b n7:propeptide n7:hemoglobin%20digestion n7:ph
n4:kodStatuVydavatele
GB - Spojené království Velké Británie a Severního Irska
n4:kontrolniKodProRIV
[1E8609FB7DF3]
n4:nazevZdroje
Structure
n4:obor
n5:CE
n4:pocetDomacichTvurcuVysledku
1
n4:pocetTvurcuVysledku
10
n4:projekt
n10:LH12023 n10:GA203%2F09%2F1585 n10:LO1302
n4:rokUplatneniVysledku
n15:2014
n4:svazekPeriodika
22
n4:tvurceVysledku
Jílková, Adéla Caffrey, Conor R. Mareš, Michael Horn, Martin McKerrow, James H. Brynda, Jiří Fajtová, Pavla Marešová, Lucie Vondrášek, Jiří Řezáčová, Pavlína
n4:wos
000345898700012
s:issn
0969-2126
s:numberOfPages
13
n18:doi
10.1016/j.str.2014.09.015
n17:organizacniJednotka
11310