ALK2 receptor kinase association with FKBP12.6 is structurally conserved with the ALK2-FKBP12 complex
The immunophilin FKBP12 is a known inhibitor of type I BMP and TGF-β receptors that competes for binding with their substrate SMADs. FKBP12 and the close paralog FKBP12.6 additionally assemble with ryanodine receptors to control Ca2+ release. Binding of FKBP12.6 to BMP/TGF-β receptors has yet to be...
| Main Authors: | , , , |
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| Format: | Journal article |
| Language: | English |
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MDPI
2021
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| _version_ | 1797084011250581504 |
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| author | Williams, E Riesebos, E Kerr, G Bullock, AN |
| author_facet | Williams, E Riesebos, E Kerr, G Bullock, AN |
| author_sort | Williams, E |
| collection | OXFORD |
| description | The immunophilin FKBP12 is a known inhibitor of type I BMP and TGF-β receptors that competes for binding with their substrate SMADs. FKBP12 and the close paralog FKBP12.6 additionally assemble with ryanodine receptors to control Ca2+ release. Binding of FKBP12.6 to BMP/TGF-β receptors has yet to be investigated, but appears plausible given its high sequence similarity to FKBP12. Here, we found that FKBP12.6 can assemble with BMP and TGF-β-family type I receptors, but not with type II receptors. Cellular immunoprecipitation confirmed similar binding of FKBP12 and FKBP12.6 to the BMP receptor ALK2 (ACVR1), a known target of mutations in the congenital syndrome fibrodysplasia ossificans progressiva (FOP), as well as the pediatric brain tumor diffuse intrinsic pontine glioma (DIPG). SEC-MALS analyses using purified proteins indicated a direct 1:1 interaction between FKBP12.6 and the receptor’s cytoplasmic domains. The 2.17 Å structure of this ALK2-FKBP12.6 complex bound to the inhibitor dorsomorphin showed FKBP12.6 binding to the GS domain of ALK2 in a manner equivalent to the FKBP12 complex, with ALK2 residues Phe198 and Leu199 extending into the FK506-binding pocket of FKBP12.6. These findings suggest a level of redundancy in FKBP-family regulation of BMP and TGF-β signaling. |
| first_indexed | 2024-03-07T01:49:39Z |
| format | Journal article |
| id | oxford-uuid:99a286ab-23e1-4efe-acec-40882b2aa1c3 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T01:49:39Z |
| publishDate | 2021 |
| publisher | MDPI |
| record_format | dspace |
| spelling | oxford-uuid:99a286ab-23e1-4efe-acec-40882b2aa1c32022-03-27T00:15:43ZALK2 receptor kinase association with FKBP12.6 is structurally conserved with the ALK2-FKBP12 complexJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:99a286ab-23e1-4efe-acec-40882b2aa1c3EnglishSymplectic ElementsMDPI2021Williams, ERiesebos, EKerr, GBullock, ANThe immunophilin FKBP12 is a known inhibitor of type I BMP and TGF-β receptors that competes for binding with their substrate SMADs. FKBP12 and the close paralog FKBP12.6 additionally assemble with ryanodine receptors to control Ca2+ release. Binding of FKBP12.6 to BMP/TGF-β receptors has yet to be investigated, but appears plausible given its high sequence similarity to FKBP12. Here, we found that FKBP12.6 can assemble with BMP and TGF-β-family type I receptors, but not with type II receptors. Cellular immunoprecipitation confirmed similar binding of FKBP12 and FKBP12.6 to the BMP receptor ALK2 (ACVR1), a known target of mutations in the congenital syndrome fibrodysplasia ossificans progressiva (FOP), as well as the pediatric brain tumor diffuse intrinsic pontine glioma (DIPG). SEC-MALS analyses using purified proteins indicated a direct 1:1 interaction between FKBP12.6 and the receptor’s cytoplasmic domains. The 2.17 Å structure of this ALK2-FKBP12.6 complex bound to the inhibitor dorsomorphin showed FKBP12.6 binding to the GS domain of ALK2 in a manner equivalent to the FKBP12 complex, with ALK2 residues Phe198 and Leu199 extending into the FK506-binding pocket of FKBP12.6. These findings suggest a level of redundancy in FKBP-family regulation of BMP and TGF-β signaling. |
| spellingShingle | Williams, E Riesebos, E Kerr, G Bullock, AN ALK2 receptor kinase association with FKBP12.6 is structurally conserved with the ALK2-FKBP12 complex |
| title | ALK2 receptor kinase association with FKBP12.6 is structurally conserved with the ALK2-FKBP12 complex |
| title_full | ALK2 receptor kinase association with FKBP12.6 is structurally conserved with the ALK2-FKBP12 complex |
| title_fullStr | ALK2 receptor kinase association with FKBP12.6 is structurally conserved with the ALK2-FKBP12 complex |
| title_full_unstemmed | ALK2 receptor kinase association with FKBP12.6 is structurally conserved with the ALK2-FKBP12 complex |
| title_short | ALK2 receptor kinase association with FKBP12.6 is structurally conserved with the ALK2-FKBP12 complex |
| title_sort | alk2 receptor kinase association with fkbp12 6 is structurally conserved with the alk2 fkbp12 complex |
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