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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
SmCL3, a gastrodermal cysteine protease of the human blood fluke Schistosoma mansoni
PLoS Neglected Tropical Diseases, Volume 3, No. 6, Article e449, Year 2009
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Description
Background: Blood flukes of the genus Schistosoma are platyhelminth parasites that infect 200 million people worldwide. Digestion of nutrients from the host bloodstream is essential for parasite development and reproduction. A network of proteolytic enzymes (proteases) facilitates hydrolysis of host hemoglobin and serum proteins. Methodology/Principal Findings: We identified a new cathepsin L termed SmCL3 using PCR strategies based on S. mansoni EST sequence data. An ortholog is present in Schistosoma japonicum. SmCL3 was heterologously expressed as an active enzyme in the yeast, Pichia pastoris. Recombinant SmCL3 has a broad pH activity range against peptidyl substrates and is inhibited by Clan CA protease inhibitors. Consistent with a function in degrading host proteins, SmCL3 hydrolyzes serum albumin and hemoglobin, is localized to the adult gastrodermis, and is expressed mainly in those life stages infecting the mammalian host. The predominant form of SmCL3 in the parasite exists as a zymogen, which is unusual for proteases. This zymogen includes an unusually long prodomain with alpha helical secondary structure motifs. The striking specificity of SmCL3 for amino acids with large aromatic side chains (Trp and Tyr) at the P2 substrate position, as determined with positional scanning-synthetic combinatorial library, is consistent with a molecular model that shows a large and deep S2 pocket. A sequence similarity network (SSN) view clusters SmCL3 and other cathepsins L in accordance with previous large-scale phylogenetic analyses that identify six super kingdoms. Conclusions/Significance: SmCL3 is a gut-associated cathepsin L that may contribute to the network of proteases involved in degrading host blood proteins as nutrients. Furthermore, this enzyme exhibits some unusual sequence and biophysical features that may result in additional functions. The visualization of network inter-relationships among cathepsins L suggests that these enzymes are suitable 'marker sequences' for inclusion in future phylogenetic analyses. © 2009 Dvořák et al.
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC2685030/bin/pntd.0000449.s001.zip
https://efashare.b-cdn.net/share/pmc/articles/PMC2685030/bin/pntd.0000449.s002.doc
Authors & Co-Authors
Dvořák, Jan
United States, Berkeley
California Institute for Quantitative Biosciences
Mashiyama, Susan T.
United States, Berkeley
California Institute for Quantitative Biosciences
Sajid, Mohammed
United States, Berkeley
California Institute for Quantitative Biosciences
Netherlands, Leiden
Leids Universitair Medisch Centrum
Braschi, Simon
United States, Berkeley
California Institute for Quantitative Biosciences
United Kingdom, Cambridge
Abcam Plc
Delcroix, Melaine
United States, Berkeley
California Institute for Quantitative Biosciences
United States, Berkeley
University of California, Berkeley
Schneider, Eric L.
United States, Berkeley
California Institute for Quantitative Biosciences
McKerrow, Wilson H.
United States, Berkeley
California Institute for Quantitative Biosciences
United States, Haverford
Haverford College
Bahgat, Mahmoud Mohamed
Egypt, Giza
National Research Centre
Hansell, Elizabeth
United States, Berkeley
California Institute for Quantitative Biosciences
Babbitt, Patricia Clement
United States, Berkeley
California Institute for Quantitative Biosciences
Craik, Charles S.
United States, Berkeley
California Institute for Quantitative Biosciences
McKerrow, James Hobson
United States, Berkeley
California Institute for Quantitative Biosciences
Caffrey, Conor Robert
United States, Berkeley
California Institute for Quantitative Biosciences
Statistics
Citations: 49
Authors: 13
Affiliations: 6
Identifiers
Doi:
10.1371/journal.pntd.0000449