ALK2 Receptor Kinase Association with FKBP12.6 Is Structurally Conserved with the ALK2-FKBP12 Complex
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Centre for Medicines Discovery, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK
2
Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 BT Amsterdam, The Netherlands
*
Author to whom correspondence should be addressed.
†
Present address: Room 5804, Level 5 John Radcliffe Hospital, Headley Way, Oxford, OX3 9DU, UK.
Academic Editor: Roberto Ravazzolo
Biomedicines 2021, 9(2), 129; https://doi.org/10.3390/biomedicines9020129
Received: 31 December 2020
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Revised: 25 January 2021
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Accepted: 26 January 2021
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Published: 29 January 2021
(This article belongs to the Special Issue Fibrodysplasia Ossificans Progressiva: Studies on Disease Mechanism towards Novel Therapeutic Approaches)
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.
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MDPI and ACS Style
Williams, E.; Riesebos, E.; Kerr, G.; Bullock, A.N. ALK2 Receptor Kinase Association with FKBP12.6 Is Structurally Conserved with the ALK2-FKBP12 Complex. Biomedicines 2021, 9, 129. https://doi.org/10.3390/biomedicines9020129
AMA Style
Williams E, Riesebos E, Kerr G, Bullock AN. ALK2 Receptor Kinase Association with FKBP12.6 Is Structurally Conserved with the ALK2-FKBP12 Complex. Biomedicines. 2021; 9(2):129. https://doi.org/10.3390/biomedicines9020129
Chicago/Turabian StyleWilliams, Eleanor, Elise Riesebos, Georgina Kerr, and Alex N. Bullock. 2021. "ALK2 Receptor Kinase Association with FKBP12.6 Is Structurally Conserved with the ALK2-FKBP12 Complex" Biomedicines 9, no. 2: 129. https://doi.org/10.3390/biomedicines9020129
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