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Danielle Derocq - One of the best experts on this subject based on the ideXlab platform.
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Additional file 5: of Immunotherapy of triple-negative breast cancer with CATHepsin D-targeting antibodies
2019Co-Authors: Yahya Ashraf, Hanane Mansouri, Valérie Laurent-matha, Lindsay Alcaraz, Pascal Roger, Séverine Guiu, Danielle Derocq, Gautier Robin, Henri-alexandre Michaud, Helène DelpechAbstract:Figure S4. Generation of anti-CATH-D human scFv fragments by phage display. (A) Enrichment of anti-CATH-D polyclonal scFv fragments by phage display. ScFv phages specific for human mature 34+14-kDa CATH-D were selected and enriched in four biopanning rounds, and analyzed by ELISA using a HRP-labeled anti-M13 antibody. BSA, negative antigen. (B) Selection of anti-CATH-D monoclonal scFv fragments by ELISA. ELISA performed using bacterial culture supernatants of the best scFv clones (5 out of 400 screened clones) and recombinant human mature 34+14-kDa CATH-D and 52-kDa pro-CATH-D. Binding of the scFv clones to CATH-D was detected with a HRP-labeled anti-Myc antibody. BSA, negative antigen; IR, irrelevant scFv from the screen. (C) Purification of the anti-human CATH-D scFv fragments. His-tagged anti-CATH-D scFv fragments were purified using TALON resin, resolved by 12% SDS-PAGE and stained with Coomassie blue. (D) Binding of purified anti-CATH-D monoclonal scFv antibodies to human CATH-D from MDA-MB-231 cells. Binding of purified anti-CATH-D scFv antibodies to secreted pro-CATH-D and cellular CATH-D from MDA-MB-231 cells was assayed by ELISA using an anti-His HRP-conjugated antibody (left panel). BSA, negative antigen; IR, irrelevant scFv; n = 3 Right panel, a whole cell lysate (10 μg) and conditioned medium (80 μl) from MDA-MB-231 cells were analyzed by 12% SDS-PAGE and immunoblotting using a polyclonal anti-mouse CATH-D (sc-6486) antibody that cross-reacts with human CATH-D (52-, 48- and 34-kDa isoforms). Mr, relative molecular mass (kDa). (E) Anti-human CATH-D monoclonal scFv antibodies cross-react with mouse CATH-D. Binding of anti-CATH-D scFv antibodies to CATH-D from mouse embryonic fibroblasts (MEFs) was monitored by ELISA using an anti His HRP-conjugated antibody (left panel). BSA, negative antigen; n = 3. Right panel, whole mouse embryonic fibroblast lysate (25 μg) was analyzed by 12% SDS-PAGE and immunoblotting using a polyclonal anti-mouse CATH-D (sc-6486) antibody against the mouse cellular CATH-D 48- and 34-kDa isoforms. Mr, relative molecular mass (kDa). (PPTX 433 kb
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Additional file 2: of Immunotherapy of triple-negative breast cancer with CATHepsin D-targeting antibodies
2019Co-Authors: Yahya Ashraf, Hanane Mansouri, Valérie Laurent-matha, Lindsay Alcaraz, Pascal Roger, Séverine Guiu, Danielle Derocq, Gautier Robin, Henri-alexandre Michaud, Helène DelpechAbstract:Figure S1. CATH-D expression in different BC subtypes. Total CATH-D expression was determined in 159 whole cytosols from primary BC biopsies (HR+/HER2+ (n = 38); HR-/HER2+ (n = 38); HR+/HER2- (n = 42); HR-/HER- (n = 41)) by sandwich ELISA with the immobilized anti-human CATH-D D7E3 antibody and the anti-human CATH-D M1G8 antibody coupled to HRP. HR= ER + PR. Mean ± SEM. (PPTX 61 kb
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Additional file 10: of Immunotherapy of triple-negative breast cancer with CATHepsin D-targeting antibodies
2019Co-Authors: Yahya Ashraf, Hanane Mansouri, Valérie Laurent-matha, Lindsay Alcaraz, Pascal Roger, Séverine Guiu, Danielle Derocq, Gautier Robin, Henri-alexandre Michaud, Helène DelpechAbstract:Figure S9. Binding of F1Fc to pro-CATH-D secreted from MDA-MB-231 cells. Sandwich ELISA in which pro-CATH-D from conditioned medium of MDA-MB-231 cells was added to wells pre-coated with the anti-pro-CATH-D M2E8 mouse monoclonal antibody in the presence of F1Fc (1μg/ml) or F1 (1μg/ml). Binding of F1Fc and F1 to pro-CATH-D was revealed with an anti-human Fc antibody conjugated to HRP. RTX, rituximab (negative control antibody). (PPTX 56 kb
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Nuclear CATHepsin D enhances TRPS1 transcriptional repressor function to regulate cell cycle progression and transformation in human breast cancer cells
Oncotarget, 2015Co-Authors: Anne-sophie Bach, Valérie Laurent-matha, Danielle Derocq, Sophie Pattingre, Philippe Montcourrier, Salwa Sebti, Béatrice Orsetti, Charles Theillet, Celine Gongora, Eva IbingAbstract:The lysosomal protease CATHepsin D (CATH-D) is overproduced in breast cancer cells (BCC) and supports tumor growth and metastasis formation. Here, we describe the mechanism whereby CATH-D is accumulated in the nucleus of ERα-positive (ER+) BCC. We identified TRPS1 (tricho-rhino-phalangeal-syndrome 1), a repressor of GATA-mediated transcription, and BAT3 (Scythe/BAG6), a nucleo-cytoplasmic shuttling chaperone protein, as new CATH-D-interacting nuclear proteins. CATH-D binds to BAT3 in ER+ BCC and they partially co-localize at the surface of lysosomes and in the nucleus. BAT3 silencing inhibits CATH-D accumulation in the nucleus, indicating that CATH-D nuclear targeting is controlled by BAT3. Fully mature CATH-D also binds to full-length TRPS1 and they co-localize in the nucleus of ER+ BCC where they are associated with chromatin. Using the LexA-VP16 fusion co-activator reporter assay, we then show that CATH-D acts as a transcriptional repressor, independently of its catalytic activity. Moreover, microarray analysis of BCC in which CATH-D and/or TRPS1 expression were silenced indicated that CATH-D enhances TRPS1-mediated repression of several TRPS1-regulated genes implicated in carcinogenesis, including PTHrP, a canonical TRPS1 gene target. In addition, co-silencing of TRPS1 and CATH-D in BCC affects the transcription of cell cycle, proliferation and transformation genes, and impairs cell cycle progression and soft agar colony formation. These findings indicate that CATH-D acts as a nuclear transcriptional cofactor of TRPS1 to regulate ER+ BCC proliferation and transformation in a non-proteolytic manner.
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CATHepsin D is partly endocytosed by the LRP1 receptor and inhibits LRP1-regulated intramembrane proteolysis.
Oncogene, 2012Co-Authors: Danielle Derocq, Christine Prebois, Melanie Beaujouin, Valérie Laurent-matha, Sophie Pattingre, Gary Smith, Emmanuelle Liaudet-coopmanAbstract:The aspartic protease CATHepsin-D (CATH-D) is a marker of poor prognosis in breast cancer that is overexpressed and hypersecreted by human breast cancer cells. Secreted pro-CATH-D binds to the extracellular domain of the β-chain of the LDL receptor-related protein-1 (LRP1) in fibroblasts. The LRP1 receptor has an 85-kDa transmembrane β-chain and a noncovalently attached 515-kDa extracellular α-chain. LRP1 acts by (1) internalizing many ligands via its α-chain, (2) activating signaling pathways by phosphorylating the LRP1β-chain tyrosine and (3) modulating gene transcription by regulated intramembrane proteolysis (RIP) of its β-chain. LRP1 RIP involves two cleavages: the first liberates the LRP1 ectodomain to give a membrane-associated form, LRP1β-CTF, and the second generates the LRP1β-intracellular domain, LRP1β-ICD, that modulates gene transcription. Here, we investigated the endocytosis of pro-CATH-D by LRP1 and the effect of pro-CATH-D/LRP1β interaction on LRP1β tyrosine phosphorylation and/or LRP1β RIP. Our results indicate that pro-CATH-D was partially endocytosed by LRP1 in fibroblasts. However, pro-CATH-D and ectopic CATH-D did not stimulate phosphorylation of the LRP1β-chain tyrosine. Interestingly, ectopic CATH-D and its catalytically inactive (D231N)CATH-D, and pro-(D231N)CATH-D all significantly inhibited LRP1 RIP by preventing LRP1β-CTF production. Thus, CATH-D inhibits LRP1 RIP independently of its catalytic activity by blocking the first cleavage. As CATH-D triggers fibroblast outgrowth by LRP1, we propose that CATH-D modulates the growth of fibroblasts by inhibiting LRP1 RIP in the breast tumor microenvironment.
Christine A Orengo - One of the best experts on this subject based on the ideXlab platform.
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Extending CATH: increasing coverage of the protein structure universe and linking structure with function.
Nucleic acids research, 2010Co-Authors: Alison Cuff, Nicholas Furnham, Ian Sillitoe, Tony Lewis, Andrew B Clegg, Robert Rentzsch, Marialuisa Pellegrini-calace, David Jones, Janet Thornton, Christine A OrengoAbstract:CATH version 3.3 (class, architecture, topology, homology) contains 128,688 domains, 2386 homologous superfamilies and 1233 fold groups, and reflects a major focus on classifying structural genomics (SG) structures and transmembrane proteins, both of which are likely to add structural novelty to the database and therefore increase the coverage of protein fold space within CATH. For CATH version 3.4 we have significantly improved the presentation of sequence information and associated functional information for CATH superfamilies. The CATH superfamily pages now reflect both the functional and structural diversity within the superfamily and include structural alignments of close and distant relatives within the superfamily, annotated with functional information and details of conserved residues. A significantly more efficient search function for CATH has been established by implementing the search server Solr (http://lucene.apache.org/solr/). The CATH v3.4 webpages have been built using the Catalyst web framework.
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The CATH extended protein-family database: providing structural annotations for genome sequences
Protein science : a publication of the Protein Society, 2009Co-Authors: Frances M. G. Pearl, David A. Lee, James E. Bray, Daniel W. A. Buchan, Adrian J. Shepherd, Christine A OrengoAbstract:An automatic sequence search and analysis protocol (DomainFinder) based on PSI-BLAST and IMPALA, and using conservative thresholds, has been developed for reliably integrating gene sequences from GenBank into their respective structural families within the CATH domain database (http://www.biochem.ucl.ac.uk/bsm/CATH_new). DomainFinder assigns a new gene sequence to a CATH homologous superfamily provided that PSI-BLAST identifies a clear relationship to at least one other Protein Data Bank sequence within that superfamily. This has resulted in an expansion of the CATH protein family database (CATH-PFDB v1.6) from 19,563 domain structures to 176,597 domain sequences. A further 50,000 putative homologous relationships can be identified using less stringent cut-offs and these relationships are maintained within neighbour tables in the CATH Oracle database, pending further evidence of their suggested evolutionary relationship. Analysis of the CATH-PFDB has shown that only 15% of the sequence families are close enough to a known structure for reliable homology modeling. IMPALA/PSI-BLAST profiles have been generated for each of the sequence families in the expanded CATH-PFDB and a web server has been provided so that new sequences may be scanned against the profile library and be assigned to a structure and homologous superfamily.
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The CATH classification revisited--architectures reviewed and new ways to characterize structural divergence in superfamilies.
Nucleic acids research, 2008Co-Authors: Alison Cuff, Ian Sillitoe, Tony Lewis, Janet Thornton, Oliver C Redfern, Richard Garratt, Christine A OrengoAbstract:The latest version of CATH (class, architecture, topology, homology) (version 3.2), released in July 2008 (http://www.CATHdb.info), contains 114,215 domains, 2178 Homologous superfamilies and 1110 fold groups. We have assigned 20,330 new domains, 87 new homologous superfamilies and 26 new folds since CATH release version 3.1. A total of 28,064 new domains have been assigned since our NAR 2007 database publication (CATH version 3.0). The CATH website has been completely redesigned and includes more comprehensive documentation. We have revisited the CATH architecture level as part of the development of a 'Protein Chart' and present information on the population of each architecture. The CATHEDRAL structure comparison algorithm has been improved and used to characterize structural diversity in CATH superfamilies and structural overlaps between superfamilies. Although the majority of superfamilies in CATH are not structurally diverse and do not overlap significantly with other superfamilies, approximately 4% of superfamilies are very diverse and these are the superfamilies that are most highly populated in both the PDB and in the genomes. Information on the degree of structural diversity in each superfamily and structural overlaps between superfamilies can now be downloaded from the CATH website.
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The CATH domain structure database
Encyclopedia of Genetics Genomics Proteomics and Bioinformatics, 2005Co-Authors: Frances M. G. Pearl, Christopher Bennett, Christine A OrengoAbstract:The CATH database of protein domain structures (http://www.biochem.ucl.ac.uk/bsm/CATH/) currently contains 60 435 domain structures classified into 917 fold groups, 1606 superfamilies, and 5202 sequence families. Recent developments include improved methods for rapidly recognizing domain boundaries in multidomain proteins. These exploit the principle of domain recurrence during evolution. Algorithms have been developed that identify these regions using a fast method that compares secondary structure arrangements between proteins (CATHEDRAL). In a recent CATH release, 75% of protein chains from the Protein Data Bank (PDB), with no significant sequence similarity to entries in CATH, had domains that could be recognized using this approach. Since domain boundary assignment is a significant bottleneck in the classification of new structures, CATHEDRAL will also help increase the frequency of CATH updates. CATH has recently been used to provide structural annotations for completed genomes. The Web-based Gene3D resource assigns complete and partial genome sequences, from 120 completed genomes, to CATH domain structure superfamilies. Keywords: protein structure classification and comparison; domain boundary recognition
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Assigning genomic sequences to CATH.
Nucleic acids research, 2000Co-Authors: Frances M. G. Pearl, Ian Sillitoe, Janet M. Thornton, David A. Lee, James E. Bray, Annabel E. Todd, Andrew Harrison, Christine A OrengoAbstract:We report the latest release (version 1.6) of the CATH protein domains database (http://www.biochem.ucl.ac.uk/bsm/CATH ). This is a hierarchical classification of 18 577 domains into evolutionary families and structural groupings. We have identified 1028 homologous superfamilies in which the proteins have both structural, and sequence or functional similarity. These can be further clustered into 672 fold groups and 35 distinct architectures. Recent developments of the database include the generation of 3D templates for recognising structural relatives in each fold group, which has led to significant improvements in the speed and accuracy of updating the database and also means that less manual validation is required. We also report the establishment of the CATH-PFDB (Protein Family Database), which associates 1D sequences with the 3D homologous superfamilies. Sequences showing identifiable homology to entries in CATH have been extracted from GenBank using PSI-BLAST. A CATH-PSIBLAST server has been established, which allows you to scan a new sequence against the database. The CATH Dictionary of Homologous Superfamilies (DHS), which contains validated multiple structural alignments annotated with consensus functional information for evolutionary protein superfamilies, has been updated to include annotations associated with sequence relatives identified in GenBank. The DHS is a powerful tool for considering the variation of functional properties within a given CATH superfamily and in deciding what functional properties may be reliably inherited by a newly identified relative.
Ian Sillitoe - One of the best experts on this subject based on the ideXlab platform.
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CATH: increased structural coverage of functional space.
Nucleic acids research, 2020Co-Authors: Ian Sillitoe, Paul Ashford, Nicola Bordin, Natalie Dawson, Vaishali P Waman, Harry M Scholes, Camilla S M Pang, Laurel Woodridge, Clemens Rauer, Neeladri SenAbstract:CATH (https://www.CATHdb.info) identifies domains in protein structures from wwPDB and classifies these into evolutionary superfamilies, thereby providing structural and functional annotations. There are two levels: CATH-B, a daily snapshot of the latest domain structures and superfamily assignments, and CATH+, with additional derived data, such as predicted sequence domains, and functionally coherent sequence subsets (Functional Families or FunFams). The latest CATH+ release, version 4.3, significantly increases coverage of structural and sequence data, with an addition of 65,351 fully-classified domains structures (+15%), providing 500 238 structural domains, and 151 million predicted sequence domains (+59%) assigned to 5481 superfamilies. The FunFam generation pipeline has been re-engineered to cope with the increased influx of data. Three times more sequences are captured in FunFams, with a concomitant increase in functional purity, information content and structural coverage. FunFam expansion increases the structural annotations provided for experimental GO terms (+59%). We also present CATH-FunVar web-pages displaying variations in protein sequences and their proximity to known or predicted functional sites. We present two case studies (1) putative cancer drivers and (2) SARS-CoV-2 proteins. Finally, we have improved links to and from CATH including SCOP, InterPro, Aquaria and 2DProt.
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CATH: Comprehensive structural and functional annotations for genome sequences
Nucleic Acids Research, 2015Co-Authors: Ian Sillitoe, Tony E. Lewis, Alison Cuff, Sayoni Das, Paul Ashford, Natalie L. Dawson, Nicholas Furnham, Roman A. Laskowski, David Lee, Jonathan G. LeesAbstract:The latest version of the CATH-Gene3D protein structure classification database (4.0, http://www.CATHdb.info) provides annotations for over 235 000 protein domain structures and includes 25 million domain predictions. This article provides an update on the major developments in the 2 years since the last publication in this journal including: significant improvements to the predictive power of our functional families (FunFams); the release of our ‘current’ putative domain assignments (CATH-B); a new, strictly non-redundant data set of CATH domains suitable for homology benchmarking experiments (CATH-40) and a number of improvements to the web pages.
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New functional families (FunFams) in CATH to improve the mapping of conserved functional sites to 3D structures
Nucleic Acids Research, 2012Co-Authors: Ian Sillitoe, Tony E. Lewis, Alison Cuff, Natalie L. Dawson, Nicholas Furnham, Jonathan G. Lees, Benoit H. Dessailly, David A. Lee, Romain A. Studer, Robert RentzschAbstract:CATH version 3.5 (Class, Architecture, Topology, Homology, available at http://www.CATHdb.info/) contains 173 536 domains, 2626 homologous superfamilies and 1313 fold groups. When focusing on structural genomics (SG) structures, we observe that the number of new folds for CATH v3.5 is slightly less than for previous releases, and this observation suggests that we may now know the majority of folds that are easily accessible to structure determination. We have improved the accuracy of our functional family (FunFams) sub-classification method and the CATH sequence domain search facility has been extended to provide FunFam annotations for each domain. The CATH website has been redesigned. We have improved the display of functional data and of conserved sequence features associated with FunFams within each CATH superfamily.
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Extending CATH: increasing coverage of the protein structure universe and linking structure with function.
Nucleic acids research, 2010Co-Authors: Alison Cuff, Nicholas Furnham, Ian Sillitoe, Tony Lewis, Andrew B Clegg, Robert Rentzsch, Marialuisa Pellegrini-calace, David Jones, Janet Thornton, Christine A OrengoAbstract:CATH version 3.3 (class, architecture, topology, homology) contains 128,688 domains, 2386 homologous superfamilies and 1233 fold groups, and reflects a major focus on classifying structural genomics (SG) structures and transmembrane proteins, both of which are likely to add structural novelty to the database and therefore increase the coverage of protein fold space within CATH. For CATH version 3.4 we have significantly improved the presentation of sequence information and associated functional information for CATH superfamilies. The CATH superfamily pages now reflect both the functional and structural diversity within the superfamily and include structural alignments of close and distant relatives within the superfamily, annotated with functional information and details of conserved residues. A significantly more efficient search function for CATH has been established by implementing the search server Solr (http://lucene.apache.org/solr/). The CATH v3.4 webpages have been built using the Catalyst web framework.
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The CATH classification revisited--architectures reviewed and new ways to characterize structural divergence in superfamilies.
Nucleic acids research, 2008Co-Authors: Alison Cuff, Ian Sillitoe, Tony Lewis, Janet Thornton, Oliver C Redfern, Richard Garratt, Christine A OrengoAbstract:The latest version of CATH (class, architecture, topology, homology) (version 3.2), released in July 2008 (http://www.CATHdb.info), contains 114,215 domains, 2178 Homologous superfamilies and 1110 fold groups. We have assigned 20,330 new domains, 87 new homologous superfamilies and 26 new folds since CATH release version 3.1. A total of 28,064 new domains have been assigned since our NAR 2007 database publication (CATH version 3.0). The CATH website has been completely redesigned and includes more comprehensive documentation. We have revisited the CATH architecture level as part of the development of a 'Protein Chart' and present information on the population of each architecture. The CATHEDRAL structure comparison algorithm has been improved and used to characterize structural diversity in CATH superfamilies and structural overlaps between superfamilies. Although the majority of superfamilies in CATH are not structurally diverse and do not overlap significantly with other superfamilies, approximately 4% of superfamilies are very diverse and these are the superfamilies that are most highly populated in both the PDB and in the genomes. Information on the degree of structural diversity in each superfamily and structural overlaps between superfamilies can now be downloaded from the CATH website.
Alison Cuff - One of the best experts on this subject based on the ideXlab platform.
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CATH: Comprehensive structural and functional annotations for genome sequences
Nucleic Acids Research, 2015Co-Authors: Ian Sillitoe, Tony E. Lewis, Alison Cuff, Sayoni Das, Paul Ashford, Natalie L. Dawson, Nicholas Furnham, Roman A. Laskowski, David Lee, Jonathan G. LeesAbstract:The latest version of the CATH-Gene3D protein structure classification database (4.0, http://www.CATHdb.info) provides annotations for over 235 000 protein domain structures and includes 25 million domain predictions. This article provides an update on the major developments in the 2 years since the last publication in this journal including: significant improvements to the predictive power of our functional families (FunFams); the release of our ‘current’ putative domain assignments (CATH-B); a new, strictly non-redundant data set of CATH domains suitable for homology benchmarking experiments (CATH-40) and a number of improvements to the web pages.
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New functional families (FunFams) in CATH to improve the mapping of conserved functional sites to 3D structures
Nucleic Acids Research, 2012Co-Authors: Ian Sillitoe, Tony E. Lewis, Alison Cuff, Natalie L. Dawson, Nicholas Furnham, Jonathan G. Lees, Benoit H. Dessailly, David A. Lee, Romain A. Studer, Robert RentzschAbstract:CATH version 3.5 (Class, Architecture, Topology, Homology, available at http://www.CATHdb.info/) contains 173 536 domains, 2626 homologous superfamilies and 1313 fold groups. When focusing on structural genomics (SG) structures, we observe that the number of new folds for CATH v3.5 is slightly less than for previous releases, and this observation suggests that we may now know the majority of folds that are easily accessible to structure determination. We have improved the accuracy of our functional family (FunFams) sub-classification method and the CATH sequence domain search facility has been extended to provide FunFam annotations for each domain. The CATH website has been redesigned. We have improved the display of functional data and of conserved sequence features associated with FunFams within each CATH superfamily.
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Extending CATH: increasing coverage of the protein structure universe and linking structure with function.
Nucleic acids research, 2010Co-Authors: Alison Cuff, Nicholas Furnham, Ian Sillitoe, Tony Lewis, Andrew B Clegg, Robert Rentzsch, Marialuisa Pellegrini-calace, David Jones, Janet Thornton, Christine A OrengoAbstract:CATH version 3.3 (class, architecture, topology, homology) contains 128,688 domains, 2386 homologous superfamilies and 1233 fold groups, and reflects a major focus on classifying structural genomics (SG) structures and transmembrane proteins, both of which are likely to add structural novelty to the database and therefore increase the coverage of protein fold space within CATH. For CATH version 3.4 we have significantly improved the presentation of sequence information and associated functional information for CATH superfamilies. The CATH superfamily pages now reflect both the functional and structural diversity within the superfamily and include structural alignments of close and distant relatives within the superfamily, annotated with functional information and details of conserved residues. A significantly more efficient search function for CATH has been established by implementing the search server Solr (http://lucene.apache.org/solr/). The CATH v3.4 webpages have been built using the Catalyst web framework.
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The CATH classification revisited--architectures reviewed and new ways to characterize structural divergence in superfamilies.
Nucleic acids research, 2008Co-Authors: Alison Cuff, Ian Sillitoe, Tony Lewis, Janet Thornton, Oliver C Redfern, Richard Garratt, Christine A OrengoAbstract:The latest version of CATH (class, architecture, topology, homology) (version 3.2), released in July 2008 (http://www.CATHdb.info), contains 114,215 domains, 2178 Homologous superfamilies and 1110 fold groups. We have assigned 20,330 new domains, 87 new homologous superfamilies and 26 new folds since CATH release version 3.1. A total of 28,064 new domains have been assigned since our NAR 2007 database publication (CATH version 3.0). The CATH website has been completely redesigned and includes more comprehensive documentation. We have revisited the CATH architecture level as part of the development of a 'Protein Chart' and present information on the population of each architecture. The CATHEDRAL structure comparison algorithm has been improved and used to characterize structural diversity in CATH superfamilies and structural overlaps between superfamilies. Although the majority of superfamilies in CATH are not structurally diverse and do not overlap significantly with other superfamilies, approximately 4% of superfamilies are very diverse and these are the superfamilies that are most highly populated in both the PDB and in the genomes. Information on the degree of structural diversity in each superfamily and structural overlaps between superfamilies can now be downloaded from the CATH website.
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The CATH classification revisited--architectures reviewed and new ways to characterize structural divergence in superfamilies.
Nucleic Acids Research, 2008Co-Authors: Alison Cuff, Tony E. Lewis, Ian Sillitoe, Oliver C Redfern, Richard Garratt, Janet M. Thornton, CA OrengoAbstract:The latest version of CATH (class, architecture, topology, homology) (version 3.2), released in July 2008 (http://www.CATHdb.info), contains 1 14 215 domains, 2178 Homologous superfamilies and 1110 fold groups. We have assigned 20 330 new domains, 87 new homologous superfamilies and 26 new folds since CATH release version 3.1. A total of 28 064 new domains have been assigned since our NAR 2007 database publication (CATH version 3.0). The CATH website has been completely redesigned and includes more comprehensive documentation. We have revisited the CATH architecture level as part of the development of a ‘Protein Chart’ and present information on the population of each architecture. The CATHEDRAL structure comparison algorithm has been improved and used to characterize structural diversity in CATH superfamilies and structural overlaps between superfamilies. Although the majority of superfamilies in CATH are not structurally diverse and do not overlap significantly with other superfamilies, ~4% of superfamilies are very diverse and these are the superfamilies that are most highly populated in both the PDB and in the genomes. Information on the degree of structural diversity in each superfamily and structural overlaps between superfamilies can now be downloaded from the CATH website.
Valérie Laurent-matha - One of the best experts on this subject based on the ideXlab platform.
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Additional file 5: of Immunotherapy of triple-negative breast cancer with CATHepsin D-targeting antibodies
2019Co-Authors: Yahya Ashraf, Hanane Mansouri, Valérie Laurent-matha, Lindsay Alcaraz, Pascal Roger, Séverine Guiu, Danielle Derocq, Gautier Robin, Henri-alexandre Michaud, Helène DelpechAbstract:Figure S4. Generation of anti-CATH-D human scFv fragments by phage display. (A) Enrichment of anti-CATH-D polyclonal scFv fragments by phage display. ScFv phages specific for human mature 34+14-kDa CATH-D were selected and enriched in four biopanning rounds, and analyzed by ELISA using a HRP-labeled anti-M13 antibody. BSA, negative antigen. (B) Selection of anti-CATH-D monoclonal scFv fragments by ELISA. ELISA performed using bacterial culture supernatants of the best scFv clones (5 out of 400 screened clones) and recombinant human mature 34+14-kDa CATH-D and 52-kDa pro-CATH-D. Binding of the scFv clones to CATH-D was detected with a HRP-labeled anti-Myc antibody. BSA, negative antigen; IR, irrelevant scFv from the screen. (C) Purification of the anti-human CATH-D scFv fragments. His-tagged anti-CATH-D scFv fragments were purified using TALON resin, resolved by 12% SDS-PAGE and stained with Coomassie blue. (D) Binding of purified anti-CATH-D monoclonal scFv antibodies to human CATH-D from MDA-MB-231 cells. Binding of purified anti-CATH-D scFv antibodies to secreted pro-CATH-D and cellular CATH-D from MDA-MB-231 cells was assayed by ELISA using an anti-His HRP-conjugated antibody (left panel). BSA, negative antigen; IR, irrelevant scFv; n = 3 Right panel, a whole cell lysate (10 μg) and conditioned medium (80 μl) from MDA-MB-231 cells were analyzed by 12% SDS-PAGE and immunoblotting using a polyclonal anti-mouse CATH-D (sc-6486) antibody that cross-reacts with human CATH-D (52-, 48- and 34-kDa isoforms). Mr, relative molecular mass (kDa). (E) Anti-human CATH-D monoclonal scFv antibodies cross-react with mouse CATH-D. Binding of anti-CATH-D scFv antibodies to CATH-D from mouse embryonic fibroblasts (MEFs) was monitored by ELISA using an anti His HRP-conjugated antibody (left panel). BSA, negative antigen; n = 3. Right panel, whole mouse embryonic fibroblast lysate (25 μg) was analyzed by 12% SDS-PAGE and immunoblotting using a polyclonal anti-mouse CATH-D (sc-6486) antibody against the mouse cellular CATH-D 48- and 34-kDa isoforms. Mr, relative molecular mass (kDa). (PPTX 433 kb
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Additional file 2: of Immunotherapy of triple-negative breast cancer with CATHepsin D-targeting antibodies
2019Co-Authors: Yahya Ashraf, Hanane Mansouri, Valérie Laurent-matha, Lindsay Alcaraz, Pascal Roger, Séverine Guiu, Danielle Derocq, Gautier Robin, Henri-alexandre Michaud, Helène DelpechAbstract:Figure S1. CATH-D expression in different BC subtypes. Total CATH-D expression was determined in 159 whole cytosols from primary BC biopsies (HR+/HER2+ (n = 38); HR-/HER2+ (n = 38); HR+/HER2- (n = 42); HR-/HER- (n = 41)) by sandwich ELISA with the immobilized anti-human CATH-D D7E3 antibody and the anti-human CATH-D M1G8 antibody coupled to HRP. HR= ER + PR. Mean ± SEM. (PPTX 61 kb
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Additional file 10: of Immunotherapy of triple-negative breast cancer with CATHepsin D-targeting antibodies
2019Co-Authors: Yahya Ashraf, Hanane Mansouri, Valérie Laurent-matha, Lindsay Alcaraz, Pascal Roger, Séverine Guiu, Danielle Derocq, Gautier Robin, Henri-alexandre Michaud, Helène DelpechAbstract:Figure S9. Binding of F1Fc to pro-CATH-D secreted from MDA-MB-231 cells. Sandwich ELISA in which pro-CATH-D from conditioned medium of MDA-MB-231 cells was added to wells pre-coated with the anti-pro-CATH-D M2E8 mouse monoclonal antibody in the presence of F1Fc (1μg/ml) or F1 (1μg/ml). Binding of F1Fc and F1 to pro-CATH-D was revealed with an anti-human Fc antibody conjugated to HRP. RTX, rituximab (negative control antibody). (PPTX 56 kb
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Nuclear CATHepsin D enhances TRPS1 transcriptional repressor function to regulate cell cycle progression and transformation in human breast cancer cells
Oncotarget, 2015Co-Authors: Anne-sophie Bach, Valérie Laurent-matha, Danielle Derocq, Sophie Pattingre, Philippe Montcourrier, Salwa Sebti, Béatrice Orsetti, Charles Theillet, Celine Gongora, Eva IbingAbstract:The lysosomal protease CATHepsin D (CATH-D) is overproduced in breast cancer cells (BCC) and supports tumor growth and metastasis formation. Here, we describe the mechanism whereby CATH-D is accumulated in the nucleus of ERα-positive (ER+) BCC. We identified TRPS1 (tricho-rhino-phalangeal-syndrome 1), a repressor of GATA-mediated transcription, and BAT3 (Scythe/BAG6), a nucleo-cytoplasmic shuttling chaperone protein, as new CATH-D-interacting nuclear proteins. CATH-D binds to BAT3 in ER+ BCC and they partially co-localize at the surface of lysosomes and in the nucleus. BAT3 silencing inhibits CATH-D accumulation in the nucleus, indicating that CATH-D nuclear targeting is controlled by BAT3. Fully mature CATH-D also binds to full-length TRPS1 and they co-localize in the nucleus of ER+ BCC where they are associated with chromatin. Using the LexA-VP16 fusion co-activator reporter assay, we then show that CATH-D acts as a transcriptional repressor, independently of its catalytic activity. Moreover, microarray analysis of BCC in which CATH-D and/or TRPS1 expression were silenced indicated that CATH-D enhances TRPS1-mediated repression of several TRPS1-regulated genes implicated in carcinogenesis, including PTHrP, a canonical TRPS1 gene target. In addition, co-silencing of TRPS1 and CATH-D in BCC affects the transcription of cell cycle, proliferation and transformation genes, and impairs cell cycle progression and soft agar colony formation. These findings indicate that CATH-D acts as a nuclear transcriptional cofactor of TRPS1 to regulate ER+ BCC proliferation and transformation in a non-proteolytic manner.
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CATHepsin D is partly endocytosed by the LRP1 receptor and inhibits LRP1-regulated intramembrane proteolysis.
Oncogene, 2012Co-Authors: Danielle Derocq, Christine Prebois, Melanie Beaujouin, Valérie Laurent-matha, Sophie Pattingre, Gary Smith, Emmanuelle Liaudet-coopmanAbstract:The aspartic protease CATHepsin-D (CATH-D) is a marker of poor prognosis in breast cancer that is overexpressed and hypersecreted by human breast cancer cells. Secreted pro-CATH-D binds to the extracellular domain of the β-chain of the LDL receptor-related protein-1 (LRP1) in fibroblasts. The LRP1 receptor has an 85-kDa transmembrane β-chain and a noncovalently attached 515-kDa extracellular α-chain. LRP1 acts by (1) internalizing many ligands via its α-chain, (2) activating signaling pathways by phosphorylating the LRP1β-chain tyrosine and (3) modulating gene transcription by regulated intramembrane proteolysis (RIP) of its β-chain. LRP1 RIP involves two cleavages: the first liberates the LRP1 ectodomain to give a membrane-associated form, LRP1β-CTF, and the second generates the LRP1β-intracellular domain, LRP1β-ICD, that modulates gene transcription. Here, we investigated the endocytosis of pro-CATH-D by LRP1 and the effect of pro-CATH-D/LRP1β interaction on LRP1β tyrosine phosphorylation and/or LRP1β RIP. Our results indicate that pro-CATH-D was partially endocytosed by LRP1 in fibroblasts. However, pro-CATH-D and ectopic CATH-D did not stimulate phosphorylation of the LRP1β-chain tyrosine. Interestingly, ectopic CATH-D and its catalytically inactive (D231N)CATH-D, and pro-(D231N)CATH-D all significantly inhibited LRP1 RIP by preventing LRP1β-CTF production. Thus, CATH-D inhibits LRP1 RIP independently of its catalytic activity by blocking the first cleavage. As CATH-D triggers fibroblast outgrowth by LRP1, we propose that CATH-D modulates the growth of fibroblasts by inhibiting LRP1 RIP in the breast tumor microenvironment.