Functional Modeling of the ACVR1 (R206H) mutation in FOP
Functional Modeling of the ACVR1 (R206H) mutation in FOP
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DOI：
10.1097/blo.0b013e318126c049
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发表时间：
2007-09-01
影响因子：
4.2
通讯作者：
Kaplan, Frederick S.
中科院分区：
文献类型：
--
作者：
Groppe, Jay C.;Shore, Eileen M.;Kaplan, Frederick S.
患有进行性骨化性纤维发育不良的个体出生时患有大脚趾畸形，并在儿童时期形成异位骨骼，因为 ACVR1（一种骨形态发生蛋白 I 型受体）的甘氨酸-丝氨酸激活结构域存在相同的杂合突变。在所有受经典影响的个体中，在核苷酸 617 处用腺嘌呤取代鸟嘌呤，将 ACVR1 残基 206 处进化上保守的精氨酸替换为组氨酸，使之成为人类基因组中最高度保守的致病突变之一。为了更好地理解这种突变的分子限制和生理学意义，我们对野生型和突变型 ACVR1 进行了计算机建模。在野生型 ACVR1 模型和模板晶体结构 (T beta RI) 中，保守的精氨酸似乎与不变的天冬氨酸残基形成盐桥。尽管赖氨酸（BMPRIA 和 BMPRIB 中的保守取代）可以很容易地适应，但残基 206 处的组氨酸（如进行性骨化性纤维发育不良）仅在细胞内 pH 值降低和广泛的结构重排时才会参与与天冬氨酸的盐桥。蛋白质模型预测，用组氨酸（且仅用组氨酸）取代会在受体的激活域内产生 pH 敏感开关，从而导致进行性骨化性核发育不良中 ACVR1 的配体独立激活。
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 (T beta RI), 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 ribrodysplasia ossificans progressiva.