Modular mechanism of Wnt signaling inhibition by Wnt inhibitory factor 1.
Wnt morphogens control embryonic development and homeostasis in adult tissues. In vertebrates the N-terminal WIF domain (WIF-1(WD)) of Wnt inhibitory factor 1 (WIF-1) binds Wnt ligands. Our crystal structure of WIF-1(WD) reveals a previously unidentified binding site for phospholipid; two acyl chain...
| Main Authors: | , , , , |
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| Format: | Journal article |
| Language: | English |
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2011
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| _version_ | 1797102573829750784 |
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| author | Malinauskas, T Aricescu, A Lu, W Siebold, C Jones, E |
| author_facet | Malinauskas, T Aricescu, A Lu, W Siebold, C Jones, E |
| author_sort | Malinauskas, T |
| collection | OXFORD |
| description | Wnt morphogens control embryonic development and homeostasis in adult tissues. In vertebrates the N-terminal WIF domain (WIF-1(WD)) of Wnt inhibitory factor 1 (WIF-1) binds Wnt ligands. Our crystal structure of WIF-1(WD) reveals a previously unidentified binding site for phospholipid; two acyl chains extend deep into the domain, and the head group is exposed to the surface. Biophysical and cellular assays indicate that there is a WIF-1(WD) Wnt-binding surface proximal to the lipid head group but also implicate the five epidermal growth factor (EGF)-like domains (EGFs I-V) in Wnt binding. The six-domain WIF-1 crystal structure shows that EGFs I-V are wrapped back, interfacing with WIF-1(WD) at EGF III. EGFs II-V contain a heparan sulfate proteoglycan (HSPG)-binding site, consistent with conserved positively charged residues on EGF IV. This combination of HSPG- and Wnt-binding properties suggests a modular model for the localization of WIF-1 and for signal inhibition within morphogen gradients. |
| first_indexed | 2024-03-07T06:07:50Z |
| format | Journal article |
| id | oxford-uuid:ee723c37-b74a-471f-81ad-0818922bc428 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:07:50Z |
| publishDate | 2011 |
| record_format | dspace |
| spelling | oxford-uuid:ee723c37-b74a-471f-81ad-0818922bc4282022-03-27T11:32:51ZModular mechanism of Wnt signaling inhibition by Wnt inhibitory factor 1.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:ee723c37-b74a-471f-81ad-0818922bc428EnglishSymplectic Elements at Oxford2011Malinauskas, TAricescu, ALu, WSiebold, CJones, EWnt morphogens control embryonic development and homeostasis in adult tissues. In vertebrates the N-terminal WIF domain (WIF-1(WD)) of Wnt inhibitory factor 1 (WIF-1) binds Wnt ligands. Our crystal structure of WIF-1(WD) reveals a previously unidentified binding site for phospholipid; two acyl chains extend deep into the domain, and the head group is exposed to the surface. Biophysical and cellular assays indicate that there is a WIF-1(WD) Wnt-binding surface proximal to the lipid head group but also implicate the five epidermal growth factor (EGF)-like domains (EGFs I-V) in Wnt binding. The six-domain WIF-1 crystal structure shows that EGFs I-V are wrapped back, interfacing with WIF-1(WD) at EGF III. EGFs II-V contain a heparan sulfate proteoglycan (HSPG)-binding site, consistent with conserved positively charged residues on EGF IV. This combination of HSPG- and Wnt-binding properties suggests a modular model for the localization of WIF-1 and for signal inhibition within morphogen gradients. |
| spellingShingle | Malinauskas, T Aricescu, A Lu, W Siebold, C Jones, E Modular mechanism of Wnt signaling inhibition by Wnt inhibitory factor 1. |
| title | Modular mechanism of Wnt signaling inhibition by Wnt inhibitory factor 1. |
| title_full | Modular mechanism of Wnt signaling inhibition by Wnt inhibitory factor 1. |
| title_fullStr | Modular mechanism of Wnt signaling inhibition by Wnt inhibitory factor 1. |
| title_full_unstemmed | Modular mechanism of Wnt signaling inhibition by Wnt inhibitory factor 1. |
| title_short | Modular mechanism of Wnt signaling inhibition by Wnt inhibitory factor 1. |
| title_sort | modular mechanism of wnt signaling inhibition by wnt inhibitory factor 1 |
| work_keys_str_mv | AT malinauskast modularmechanismofwntsignalinginhibitionbywntinhibitoryfactor1 AT aricescua modularmechanismofwntsignalinginhibitionbywntinhibitoryfactor1 AT luw modularmechanismofwntsignalinginhibitionbywntinhibitoryfactor1 AT sieboldc modularmechanismofwntsignalinginhibitionbywntinhibitoryfactor1 AT jonese modularmechanismofwntsignalinginhibitionbywntinhibitoryfactor1 |