Structure and function of the ROR2 cysteine-rich domain in vertebrate noncanonical WNT5A signaling
The receptor tyrosine kinase ROR2 mediates noncanonical WNT5A signaling to orchestrate tissue morphogenetic processes, and dysfunction of the pathway causes Robinow syndrome, brachydactyly B, and metastatic diseases. The domain(s) and mechanisms required for ROR2 function, however, remain unclear. W...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
eLife Sciences Publications
2024
|
| _version_ | 1811139866518355968 |
|---|---|
| author | Griffiths, SC Tan, J Wagner, A Blazer, LL Adams, JJ Srinivasan, S Moghisaei, S Sidhu, SS Siebold, C Ho, HH |
| author_facet | Griffiths, SC Tan, J Wagner, A Blazer, LL Adams, JJ Srinivasan, S Moghisaei, S Sidhu, SS Siebold, C Ho, HH |
| author_sort | Griffiths, SC |
| collection | OXFORD |
| description | The receptor tyrosine kinase ROR2 mediates noncanonical WNT5A signaling to orchestrate tissue morphogenetic processes, and dysfunction of the pathway causes Robinow syndrome, brachydactyly B, and metastatic diseases. The domain(s) and mechanisms required for ROR2 function, however, remain unclear. We solved the crystal structure of the extracellular cysteine-rich (CRD) and Kringle (Kr) domains of ROR2 and found that, unlike other CRDs, the ROR2 CRD lacks the signature hydrophobic pocket that binds lipids/lipid-modified proteins, such as WNTs, suggesting a novel mechanism of ligand reception. Functionally, we showed that the ROR2 CRD, but not other domains, is required and minimally sufficient to promote WNT5A signaling, and Robinow mutations in the CRD and the adjacent Kr impair ROR2 secretion and function. Moreover, using function-activating and -perturbing antibodies against the Frizzled (FZ) family of WNT receptors, we demonstrate the involvement of FZ in WNT5A-ROR signaling. Thus, ROR2 acts via its CRD to potentiate the function of a receptor super-complex that includes FZ to transduce WNT5A signals. |
| first_indexed | 2024-09-25T04:12:54Z |
| format | Journal article |
| id | oxford-uuid:e45cabbc-1612-44af-b8d1-5c3ce9e6f450 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-09-25T04:12:54Z |
| publishDate | 2024 |
| publisher | eLife Sciences Publications |
| record_format | dspace |
| spelling | oxford-uuid:e45cabbc-1612-44af-b8d1-5c3ce9e6f4502024-07-03T20:14:00ZStructure and function of the ROR2 cysteine-rich domain in vertebrate noncanonical WNT5A signalingJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:e45cabbc-1612-44af-b8d1-5c3ce9e6f450EnglishJisc Publications RoutereLife Sciences Publications2024Griffiths, SCTan, JWagner, ABlazer, LLAdams, JJSrinivasan, SMoghisaei, SSidhu, SSSiebold, CHo, HHThe receptor tyrosine kinase ROR2 mediates noncanonical WNT5A signaling to orchestrate tissue morphogenetic processes, and dysfunction of the pathway causes Robinow syndrome, brachydactyly B, and metastatic diseases. The domain(s) and mechanisms required for ROR2 function, however, remain unclear. We solved the crystal structure of the extracellular cysteine-rich (CRD) and Kringle (Kr) domains of ROR2 and found that, unlike other CRDs, the ROR2 CRD lacks the signature hydrophobic pocket that binds lipids/lipid-modified proteins, such as WNTs, suggesting a novel mechanism of ligand reception. Functionally, we showed that the ROR2 CRD, but not other domains, is required and minimally sufficient to promote WNT5A signaling, and Robinow mutations in the CRD and the adjacent Kr impair ROR2 secretion and function. Moreover, using function-activating and -perturbing antibodies against the Frizzled (FZ) family of WNT receptors, we demonstrate the involvement of FZ in WNT5A-ROR signaling. Thus, ROR2 acts via its CRD to potentiate the function of a receptor super-complex that includes FZ to transduce WNT5A signals. |
| spellingShingle | Griffiths, SC Tan, J Wagner, A Blazer, LL Adams, JJ Srinivasan, S Moghisaei, S Sidhu, SS Siebold, C Ho, HH Structure and function of the ROR2 cysteine-rich domain in vertebrate noncanonical WNT5A signaling |
| title | Structure and function of the ROR2 cysteine-rich domain in vertebrate noncanonical WNT5A signaling |
| title_full | Structure and function of the ROR2 cysteine-rich domain in vertebrate noncanonical WNT5A signaling |
| title_fullStr | Structure and function of the ROR2 cysteine-rich domain in vertebrate noncanonical WNT5A signaling |
| title_full_unstemmed | Structure and function of the ROR2 cysteine-rich domain in vertebrate noncanonical WNT5A signaling |
| title_short | Structure and function of the ROR2 cysteine-rich domain in vertebrate noncanonical WNT5A signaling |
| title_sort | structure and function of the ror2 cysteine rich domain in vertebrate noncanonical wnt5a signaling |
| work_keys_str_mv | AT griffithssc structureandfunctionoftheror2cysteinerichdomaininvertebratenoncanonicalwnt5asignaling AT tanj structureandfunctionoftheror2cysteinerichdomaininvertebratenoncanonicalwnt5asignaling AT wagnera structureandfunctionoftheror2cysteinerichdomaininvertebratenoncanonicalwnt5asignaling AT blazerll structureandfunctionoftheror2cysteinerichdomaininvertebratenoncanonicalwnt5asignaling AT adamsjj structureandfunctionoftheror2cysteinerichdomaininvertebratenoncanonicalwnt5asignaling AT srinivasans structureandfunctionoftheror2cysteinerichdomaininvertebratenoncanonicalwnt5asignaling AT moghisaeis structureandfunctionoftheror2cysteinerichdomaininvertebratenoncanonicalwnt5asignaling AT sidhuss structureandfunctionoftheror2cysteinerichdomaininvertebratenoncanonicalwnt5asignaling AT sieboldc structureandfunctionoftheror2cysteinerichdomaininvertebratenoncanonicalwnt5asignaling AT hohh structureandfunctionoftheror2cysteinerichdomaininvertebratenoncanonicalwnt5asignaling |