Functional Modeling of the ACVR1 (R206H) Mutation in FOP : Clinical Orthopaedics and Related Research® (original) (raw)

SECTION I: SYMPOSIUM: Genetics in Orthopaedics

Groppe, Jay C PhD; Shore, Eileen M PhD; Kaplan, Frederick S MD

Editor(s): Dobbs, Matthew B MD

From the*Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, TX; the †Departments of Orthopaedic Surgery and Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA; and the ‡Departments of Orthopaedic Surgery and Medicine, University of Pennsylvania School of Medicine, Department of Orthopaedic Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA.

One or more of the authors has received funding from the International FOP Association (EMS, FSK), the Center for Research in FOP & Related Disorders (JCG, EMS, FSK), the Ian Cali FOP Endowment and the Weldon Family FOP Endowment at the University of Pennsylvania (EMS, FSK ), the Isaac & Rose Nassau Professorship of Orthopaedic Molecular Medicine (FSK), and by a grant from the US National Institutes of Health (NIH RO1-AR41916) (FSK).

Correspondence to: Jay C. Groppe, PhD, University of Texas Health Science Center at San Antonio, Department of Biochemistry, 7703 Floyd Curl Drive, MSC 7760, San Antonio, TX 78229-3900. Phone: 210-567-8705; Fax: 210-567-8778; E-mail: [email protected].

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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 (TβRI), 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.

© 2007 Lippincott Williams & Wilkins, Inc.