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In vitro analyses of the dysregulated R206H ALK2 kinase-FKBP12 interaction associated with heterotopic ossification in FOP
- Source :
- Cells, tissues, organs. 194(2-4)
- Publication Year :
- 2011
-
Abstract
- A single recurrent mutation in the regulatory subdomain of a bone morphogenetic protein type I receptor kinase has been linked to heterotopic ossification in classic fibrodysplasia ossificans progressiva (FOP). As a result of a substitution at 1 residue by only 1 other side chain (Arg206His) in just 1 of the 4 type I BMP receptors (ALK2/ACVR1), soft connective tissues progressively metamorphose through an endochondral process into cartilage that is replaced by bone. The substitution of arginine for histidine, also a basic residue yet with the singular property of ionization/protonation over the physiological pH range, led to the hypothesis of an aberrant, pH-sensitive switch mechanism for the ligand-independent activation of BMP signaling through the mutant receptor kinase in patients presenting with classic FOP. To test a potential aspect of the putative pH-dependent mechanism, i.e. loss of autoinhibition of the kinase mediated by the inhibitory protein FKBP12, in vitrointeraction analyses with purified wild-type and R206H ALK2 kinase and FKBP12 proteins were performed. Interactions between the kinases and inhibitory proteins were analyzed qualitatively and quantitatively by native gel electrophoresis and HPLC size exclusion chromatography and with an optical biosensor (Octet; ForteBio). Binding of inhibitory protein by the R206H mutant was diminished 3-fold relative to the wild type kinase at a physiological pH, yet below this value (
- Subjects :
- Paper
Histology
Mutant
Biosensing Techniques
Tacrolimus Binding Protein 1A
ACVR1
Bone morphogenetic protein
medicine
Humans
Endochondral ossification
Chromatography, High Pressure Liquid
Chemistry
Kinase
Ossification, Heterotopic
Wild type
medicine.disease
BMPR2
Cell biology
Interferometry
Biochemistry
Amino Acid Substitution
Myositis Ossificans
Fibrodysplasia ossificans progressiva
Chromatography, Gel
Electrophoresis, Polyacrylamide Gel
Anatomy
Activin Receptors, Type I
Protein Binding
Subjects
Details
- ISSN :
- 14226421
- Volume :
- 194
- Issue :
- 2-4
- Database :
- OpenAIRE
- Journal :
- Cells, tissues, organs
- Accession number :
- edsair.doi.dedup.....a4ffcc4a9e477255cbce76446b2c8271