Proteomics and phylogenetic analysis of the cathepsin L protease family of the helminth pathogen Fasciola hepatica: Expansion of repertoire of virulene-associated factors

Robinson, Mark W., Tort, Jose F., Lowther, Jonathan, Donnelly, Sheila M., Wong, Emily, Xu, Weibo, Stack, Colin M., Padula, Matthew, Herbert, Ben and Dalton, John P. (2008) Proteomics and phylogenetic analysis of the cathepsin L protease family of the helminth pathogen Fasciola hepatica: Expansion of repertoire of virulene-associated factors. Molecular and Cellular Proteomics, 7 6: 1111-1123. doi:10.1074/mcp.M700560-MCP200


Author Robinson, Mark W.
Tort, Jose F.
Lowther, Jonathan
Donnelly, Sheila M.
Wong, Emily
Xu, Weibo
Stack, Colin M.
Padula, Matthew
Herbert, Ben
Dalton, John P.
Title Proteomics and phylogenetic analysis of the cathepsin L protease family of the helminth pathogen Fasciola hepatica: Expansion of repertoire of virulene-associated factors
Formatted title
Proteomics and phylogenetic analysis of the cathepsin L protease family of the helminth pathogen Fasciola hepatica: Expansion of repertoire of virulene-associated factors
Journal name Molecular and Cellular Proteomics   Check publisher's open access policy
ISSN 1535-9476
Publication date 2008-06-01
Sub-type Article (original research)
DOI 10.1074/mcp.M700560-MCP200
Open Access Status Not yet assessed
Volume 7
Issue 6
Start page 1111
End page 1123
Total pages 13
Place of publication Bethesda, MD, United States
Publisher American Society for Biochemistry and Molecular Biology
Language eng
Formatted abstract
Cathepsin L proteases secreted by the helminth pathogen Fasciola hepatica have functions in parasite virulence including tissue invasion and suppression of host immune responses. Using proteomics methods alongside phylogenetic studies we characterized the profile of cathepsin L proteases secreted by adult F. hepatica and hence identified those involved in host-pathogen interaction. Phylogenetic analyses showed that the Fasciola cathepsin L gene family expanded by a series of gene duplications followed by divergence that gave rise to three clades associated with mature adult worms (Clades 1, 2, and 5) and two clades specific to infective juvenile stages (Clades 3 and 4). Consistent with these observations our proteomics studies identified representatives from Clades 1, 2, and 5 but not from Clades 3 and 4 in adult F. hepatica secretory products. Clades 1 and 2 account for 67.39 and 27.63% of total secreted cathepsin Ls, respectively, suggesting that their expansion was positively driven and that these proteases are most critical for parasite survival and adaptation. Sequence comparison studies revealed that the expansion of cathepsin Ls by gene duplication was followed by residue changes in the S2 pocket of the active site. Our biochemical studies showed that these changes result in alterations in substrate binding and suggested that the divergence of the cathepsin L family produced a repertoire of enzymes with overlapping and complementary substrate specificities that could cleave host macromolecules more efficiently. Although the cathepsin Ls are produced as zymogens containing a prosegment and mature domain, all secreted enzymes identified by MS were processed to mature active enzymes. The prosegment region was highly conserved between the clades except at the boundary of prosegment and mature enzyme. Despite the lack of conservation at this section, sites for exogenous cleavage by asparaginyl endopeptidases and a Leu-Ser↓His motif for autocatalytic cleavage by cathepsin Ls were preserved.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
 
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Created: Thu, 15 Mar 2012, 01:32:07 EST by Susan Allen on behalf of Institute for Molecular Bioscience