Structural insights into Notch receptor-ligand interactions
Pioneering cell aggregation experiments from the Artavanis-Tsakonas group in the late 1980's localized the core ligand recognition sequence in the Drosophila Notch receptor to epidermal growth factor-like (EGF) domains 11 and 12. Since then, advances in protein expression, structure determinati...
| Auteurs principaux: | , , , , |
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| Format: | Book section |
| Langue: | English |
| Publié: |
Springer, Cham
2018
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| _version_ | 1826310724377378816 |
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| author | Handford, PA Korona, B Suckling, R Redfield, C Lea, SM |
| author_facet | Handford, PA Korona, B Suckling, R Redfield, C Lea, SM |
| author_sort | Handford, PA |
| collection | OXFORD |
| description | Pioneering cell aggregation experiments from the Artavanis-Tsakonas group in the late 1980's localized the core ligand recognition sequence in the Drosophila Notch receptor to epidermal growth factor-like (EGF) domains 11 and 12. Since then, advances in protein expression, structure determination methods and functional assays have enabled us to define the molecular basis of the core receptor/ligand interaction and given new insights into the architecture of the Notch complex at the cell surface. We now know that Notch EGF11 and 12 interact with the Delta/Serrate/LAG-2 (DSL) and C2 domains of ligand and that membrane-binding, together with additional protein-protein interactions outside the core recognition domains, are likely to fine-tune generation of the Notch signal. Furthermore, structure determination of O-glycosylated variants of Notch alone or in complex with receptor fragments, has shown that these sugars contribute directly to the binding interface, as well as to stabilizing intra-molecular domain structure, providing some mechanistic insights into the observed modulatory effects of O-glycosylation on Notch activity.Future challenges lie in determining the complete extracellular architecture of ligand and receptor in order to understand (i) how Notch/ligand complexes may form at the cell surface in response to physiological cues, (ii) the role of lipid binding in stabilizing the Notch/ligand complex, (iii) the impact of O-glycosylation on binding and signalling and (iv) to dissect the different pathologies that arise as a consequence of mutations that affect proteins involved in the Notch pathway. |
| first_indexed | 2024-03-07T07:56:14Z |
| format | Book section |
| id | oxford-uuid:8dfc2ab0-f0d3-4921-9868-0a70815943b6 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:56:14Z |
| publishDate | 2018 |
| publisher | Springer, Cham |
| record_format | dspace |
| spelling | oxford-uuid:8dfc2ab0-f0d3-4921-9868-0a70815943b62023-08-23T15:30:30ZStructural insights into Notch receptor-ligand interactionsBook sectionhttp://purl.org/coar/resource_type/c_1843uuid:8dfc2ab0-f0d3-4921-9868-0a70815943b6EnglishSymplectic Elements at OxfordSpringer, Cham2018Handford, PAKorona, BSuckling, RRedfield, CLea, SMPioneering cell aggregation experiments from the Artavanis-Tsakonas group in the late 1980's localized the core ligand recognition sequence in the Drosophila Notch receptor to epidermal growth factor-like (EGF) domains 11 and 12. Since then, advances in protein expression, structure determination methods and functional assays have enabled us to define the molecular basis of the core receptor/ligand interaction and given new insights into the architecture of the Notch complex at the cell surface. We now know that Notch EGF11 and 12 interact with the Delta/Serrate/LAG-2 (DSL) and C2 domains of ligand and that membrane-binding, together with additional protein-protein interactions outside the core recognition domains, are likely to fine-tune generation of the Notch signal. Furthermore, structure determination of O-glycosylated variants of Notch alone or in complex with receptor fragments, has shown that these sugars contribute directly to the binding interface, as well as to stabilizing intra-molecular domain structure, providing some mechanistic insights into the observed modulatory effects of O-glycosylation on Notch activity.Future challenges lie in determining the complete extracellular architecture of ligand and receptor in order to understand (i) how Notch/ligand complexes may form at the cell surface in response to physiological cues, (ii) the role of lipid binding in stabilizing the Notch/ligand complex, (iii) the impact of O-glycosylation on binding and signalling and (iv) to dissect the different pathologies that arise as a consequence of mutations that affect proteins involved in the Notch pathway. |
| spellingShingle | Handford, PA Korona, B Suckling, R Redfield, C Lea, SM Structural insights into Notch receptor-ligand interactions |
| title | Structural insights into Notch receptor-ligand interactions |
| title_full | Structural insights into Notch receptor-ligand interactions |
| title_fullStr | Structural insights into Notch receptor-ligand interactions |
| title_full_unstemmed | Structural insights into Notch receptor-ligand interactions |
| title_short | Structural insights into Notch receptor-ligand interactions |
| title_sort | structural insights into notch receptor ligand interactions |
| work_keys_str_mv | AT handfordpa structuralinsightsintonotchreceptorligandinteractions AT koronab structuralinsightsintonotchreceptorligandinteractions AT sucklingr structuralinsightsintonotchreceptorligandinteractions AT redfieldc structuralinsightsintonotchreceptorligandinteractions AT leasm structuralinsightsintonotchreceptorligandinteractions |