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 Ca<sup>2+</sup> release. Binding of FKBP12.6 to BMP/TGF-β r...
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2021-01-01
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Online Access: | https://www.mdpi.com/2227-9059/9/2/129 |
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author | Eleanor Williams Elise Riesebos Georgina Kerr Alex N. Bullock |
author_facet | Eleanor Williams Elise Riesebos Georgina Kerr Alex N. Bullock |
author_sort | Eleanor Williams |
collection | DOAJ |
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 Ca<sup>2+</sup> 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. |
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spelling | doaj.art-fd4dd3bce8d94c84919e665679fc3acf2023-12-03T15:10:50ZengMDPI AGBiomedicines2227-90592021-01-019212910.3390/biomedicines9020129ALK2 Receptor Kinase Association with FKBP12.6 Is Structurally Conserved with the ALK2-FKBP12 ComplexEleanor Williams0Elise Riesebos1Georgina Kerr2Alex N. Bullock3Centre for Medicines Discovery, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UKCentre for Medicines Discovery, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UKCentre for Medicines Discovery, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UKCentre for Medicines Discovery, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UKThe 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 Ca<sup>2+</sup> 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.https://www.mdpi.com/2227-9059/9/2/129BMPkinaseFKBP12FKBP12.6ACVR1ALK2 |
spellingShingle | Eleanor Williams Elise Riesebos Georgina Kerr Alex N. Bullock ALK2 Receptor Kinase Association with FKBP12.6 Is Structurally Conserved with the ALK2-FKBP12 Complex Biomedicines BMP kinase FKBP12 FKBP12.6 ACVR1 ALK2 |
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 |
topic | BMP kinase FKBP12 FKBP12.6 ACVR1 ALK2 |
url | https://www.mdpi.com/2227-9059/9/2/129 |
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