Structural and functional studies of LRP6 ectodomain reveal a platform for Wnt signaling.
LDL-receptor-related protein 6 (LRP6), alongside Frizzled receptors, transduces Wnt signaling across the plasma membrane. The LRP6 ectodomain comprises four tandem β-propeller-EGF-like domain (PE) pairs that harbor binding sites for Wnt morphogens and their antagonists including Dickkopf 1 (Dkk1). T...
| Main Authors: | , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2011
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| _version_ | 1797098977495089152 |
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| author | Chen, S Bubeck, D MacDonald, B Liang, W Mao, J Malinauskas, T Llorca, O Aricescu, A Siebold, C He, X Jones, E |
| author_facet | Chen, S Bubeck, D MacDonald, B Liang, W Mao, J Malinauskas, T Llorca, O Aricescu, A Siebold, C He, X Jones, E |
| author_sort | Chen, S |
| collection | OXFORD |
| description | LDL-receptor-related protein 6 (LRP6), alongside Frizzled receptors, transduces Wnt signaling across the plasma membrane. The LRP6 ectodomain comprises four tandem β-propeller-EGF-like domain (PE) pairs that harbor binding sites for Wnt morphogens and their antagonists including Dickkopf 1 (Dkk1). To understand how these multiple interactions are integrated, we combined crystallographic analysis of the third and fourth PE pairs with electron microscopy (EM) to determine the complete ectodomain structure. An extensive inter-pair interface, conserved for the first-to-second and third-to-fourth PE interactions, contributes to a compact platform-like architecture, which is disrupted by mutations implicated in developmental diseases. EM reconstruction of the LRP6 platform bound to chaperone Mesd exemplifies a binding mode spanning PE pairs. Cellular and binding assays identify overlapping Wnt3a- and Dkk1-binding surfaces on the third PE pair, consistent with steric competition, but also suggest a model in which the platform structure supports an interplay of ligands through multiple interaction sites. |
| first_indexed | 2024-03-07T05:17:14Z |
| format | Journal article |
| id | oxford-uuid:dda2e5e2-3748-4e0f-b0be-fd0e71c84c63 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T05:17:14Z |
| publishDate | 2011 |
| record_format | dspace |
| spelling | oxford-uuid:dda2e5e2-3748-4e0f-b0be-fd0e71c84c632022-03-27T09:26:25ZStructural and functional studies of LRP6 ectodomain reveal a platform for Wnt signaling.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:dda2e5e2-3748-4e0f-b0be-fd0e71c84c63EnglishSymplectic Elements at Oxford2011Chen, SBubeck, DMacDonald, BLiang, WMao, JMalinauskas, TLlorca, OAricescu, ASiebold, CHe, XJones, ELDL-receptor-related protein 6 (LRP6), alongside Frizzled receptors, transduces Wnt signaling across the plasma membrane. The LRP6 ectodomain comprises four tandem β-propeller-EGF-like domain (PE) pairs that harbor binding sites for Wnt morphogens and their antagonists including Dickkopf 1 (Dkk1). To understand how these multiple interactions are integrated, we combined crystallographic analysis of the third and fourth PE pairs with electron microscopy (EM) to determine the complete ectodomain structure. An extensive inter-pair interface, conserved for the first-to-second and third-to-fourth PE interactions, contributes to a compact platform-like architecture, which is disrupted by mutations implicated in developmental diseases. EM reconstruction of the LRP6 platform bound to chaperone Mesd exemplifies a binding mode spanning PE pairs. Cellular and binding assays identify overlapping Wnt3a- and Dkk1-binding surfaces on the third PE pair, consistent with steric competition, but also suggest a model in which the platform structure supports an interplay of ligands through multiple interaction sites. |
| spellingShingle | Chen, S Bubeck, D MacDonald, B Liang, W Mao, J Malinauskas, T Llorca, O Aricescu, A Siebold, C He, X Jones, E Structural and functional studies of LRP6 ectodomain reveal a platform for Wnt signaling. |
| title | Structural and functional studies of LRP6 ectodomain reveal a platform for Wnt signaling. |
| title_full | Structural and functional studies of LRP6 ectodomain reveal a platform for Wnt signaling. |
| title_fullStr | Structural and functional studies of LRP6 ectodomain reveal a platform for Wnt signaling. |
| title_full_unstemmed | Structural and functional studies of LRP6 ectodomain reveal a platform for Wnt signaling. |
| title_short | Structural and functional studies of LRP6 ectodomain reveal a platform for Wnt signaling. |
| title_sort | structural and functional studies of lrp6 ectodomain reveal a platform for wnt signaling |
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