Synthetic enzyme-substrate tethering obviates the Tolloid-ECM interaction during Drosophila BMP gradient formation
Members of the Tolloid family of metalloproteinases liberate BMPs from inhibitory complexes to regulate BMP gradient formation during embryonic dorsal-ventral axis patterning. Here, we determine mechanistically how Tolloid activity is regulated by its non-catalytic CUB domains in the Drosophila embr...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2015-02-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/05508 |
| _version_ | 1811181508816273408 |
|---|---|
| author | Jennifer Winstanley Annick Sawala Clair Baldock Hilary L Ashe |
| author_facet | Jennifer Winstanley Annick Sawala Clair Baldock Hilary L Ashe |
| author_sort | Jennifer Winstanley |
| collection | DOAJ |
| description | Members of the Tolloid family of metalloproteinases liberate BMPs from inhibitory complexes to regulate BMP gradient formation during embryonic dorsal-ventral axis patterning. Here, we determine mechanistically how Tolloid activity is regulated by its non-catalytic CUB domains in the Drosophila embryo. We show that Tolloid, via its N-terminal CUB domains, interacts with Collagen IV, which enhances Tolloid activity towards its substrate Sog, and facilitates Tsg-dependent stimulation of cleavage. In contrast, the two most C-terminal Tld CUB domains mediate Sog interaction to facilitate its processing as, based on our structural data, Tolloid curvature positions bound Sog in proximity to the protease domain. Having ascribed functions to the Tolloid non-catalytic domains, we recapitulate embryonic BMP gradient formation in their absence, by artificially tethering the Tld protease domain to Sog. Our studies highlight how the bipartite function of Tolloid CUB domains, in substrate and ECM interactions, fine-tune protease activity to a particular developmental context. |
| first_indexed | 2024-04-11T09:18:31Z |
| format | Article |
| id | doaj.art-c22e894d32e746c6b16452286777a735 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:18:31Z |
| publishDate | 2015-02-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-c22e894d32e746c6b16452286777a7352022-12-22T04:32:17ZengeLife Sciences Publications LtdeLife2050-084X2015-02-01410.7554/eLife.05508Synthetic enzyme-substrate tethering obviates the Tolloid-ECM interaction during Drosophila BMP gradient formationJennifer Winstanley0Annick Sawala1Clair Baldock2Hilary L Ashe3Faculty of Life Sciences, University of Manchester, Manchester, United KingdomFaculty of Life Sciences, University of Manchester, Manchester, United KingdomWellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, United KingdomFaculty of Life Sciences, University of Manchester, Manchester, United KingdomMembers of the Tolloid family of metalloproteinases liberate BMPs from inhibitory complexes to regulate BMP gradient formation during embryonic dorsal-ventral axis patterning. Here, we determine mechanistically how Tolloid activity is regulated by its non-catalytic CUB domains in the Drosophila embryo. We show that Tolloid, via its N-terminal CUB domains, interacts with Collagen IV, which enhances Tolloid activity towards its substrate Sog, and facilitates Tsg-dependent stimulation of cleavage. In contrast, the two most C-terminal Tld CUB domains mediate Sog interaction to facilitate its processing as, based on our structural data, Tolloid curvature positions bound Sog in proximity to the protease domain. Having ascribed functions to the Tolloid non-catalytic domains, we recapitulate embryonic BMP gradient formation in their absence, by artificially tethering the Tld protease domain to Sog. Our studies highlight how the bipartite function of Tolloid CUB domains, in substrate and ECM interactions, fine-tune protease activity to a particular developmental context.https://elifesciences.org/articles/05508BMPgradient formationTolloidSog/ChordinCollagen IV |
| spellingShingle | Jennifer Winstanley Annick Sawala Clair Baldock Hilary L Ashe Synthetic enzyme-substrate tethering obviates the Tolloid-ECM interaction during Drosophila BMP gradient formation eLife BMP gradient formation Tolloid Sog/Chordin Collagen IV |
| title | Synthetic enzyme-substrate tethering obviates the Tolloid-ECM interaction during Drosophila BMP gradient formation |
| title_full | Synthetic enzyme-substrate tethering obviates the Tolloid-ECM interaction during Drosophila BMP gradient formation |
| title_fullStr | Synthetic enzyme-substrate tethering obviates the Tolloid-ECM interaction during Drosophila BMP gradient formation |
| title_full_unstemmed | Synthetic enzyme-substrate tethering obviates the Tolloid-ECM interaction during Drosophila BMP gradient formation |
| title_short | Synthetic enzyme-substrate tethering obviates the Tolloid-ECM interaction during Drosophila BMP gradient formation |
| title_sort | synthetic enzyme substrate tethering obviates the tolloid ecm interaction during drosophila bmp gradient formation |
| topic | BMP gradient formation Tolloid Sog/Chordin Collagen IV |
| url | https://elifesciences.org/articles/05508 |
| work_keys_str_mv | AT jenniferwinstanley syntheticenzymesubstratetetheringobviatesthetolloidecminteractionduringdrosophilabmpgradientformation AT annicksawala syntheticenzymesubstratetetheringobviatesthetolloidecminteractionduringdrosophilabmpgradientformation AT clairbaldock syntheticenzymesubstratetetheringobviatesthetolloidecminteractionduringdrosophilabmpgradientformation AT hilarylashe syntheticenzymesubstratetetheringobviatesthetolloidecminteractionduringdrosophilabmpgradientformation |