title: Functional modeling of the ACVR1 (R206H) mutation in FOP.
abstract: Individuals with fibrodysplasia ossificans progressiva are born with malformations of the great toes and develop a heterotopic skeleton during childhood because of an identical heterozygous mutation in the glycine-serine activation domain of ACVR1, a bone morphogenetic protein type I receptor. Substitution of adenine for guanine at nucleotide 617 replaces an evolutionarily conserved arginine with histidine at residue 206 of ACVR1 in all classically affected individuals, making this one of the most highly conserved disease-causing mutations in the human genome. To better understand the molecular constraints and physiological implications of this mutation, we performed in silico modeling of wild-type and mutant ACVR1. In both the wild-type ACVR1 model and template crystal structures (TbetaRI), the conserved arginine appears to form a salt bridge with an invariant aspartate residue. Although lysine, a conservative substitution in BMPRIA and BMPRIB, can be readily accommodated, histidine at residue 206 (like in fibrodysplasia ossificans progressiva) would participate in a salt bridge with the aspartate only at decreased intracellular pH and with extensive structural rearrangement. Protein modeling predicts that substitution with histidine, and only histidine, creates a pH-sensitive switch within the activation domain of the receptor that leads to ligand-independent activation of ACVR1 in fibrodysplasia ossificans progressiva.
authors.affiliation: Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, USA. groppe@biochem.uthscsa.edu
authors.forename: Jay C
authors.initials: JC
authors.lastname: Groppe
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Shore
authors.forename: Frederick S
authors.initials: FS
authors.lastname: Kaplan
mesh_terms: D030201:Activin Receptors, Type I / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001120:Arginine / Q000737:chemistry; D003198:Computer Simulation; D006639:Histidine / Q000737:chemistry; D006801:Humans; D008957:Models, Genetic; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009221:Myositis Ossificans / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D006639:Histidine; D001120:Arginine; D017346:Protein Serine-Threonine Kinases; C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I