THERMAL-STABILITY AND FOLDING OF THE COLLAGEN TRIPLE HELIX AND THE EFFECTS OF MUTATIONS IN OSTEOGENESIS IMPERFECTA ON THE TRIPLE HELIX OF TYPE-I COLLAGEN
THERMAL-STABILITY AND FOLDING OF THE COLLAGEN TRIPLE HELIX AND THE EFFECTS OF MUTATIONS IN OSTEOGENESIS IMPERFECTA ON THE TRIPLE HELIX OF TYPE-I COLLAGEN
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DOI：
10.1002/ajmg.1320450204
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发表时间：
1993-01-15
期刊：
影响因子：
--
通讯作者：
DAVIS, JM
中科院分区：
文献类型：
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作者：
BACHINGER, HP;MORRIS, NP;DAVIS, JM
成骨不全症（OI）是一种遗传性疾病，其中90%的病例是由编码I型胶原蛋白的两个基因proalpha1和proalpha2突变引起的。I型胶原是一种三聚体分子（alpha1）2alpha2，在结构和功能上都由300 nm的三螺旋结构域主导。大多数01突变发生在该结构域，几乎所有点突变都导致其他氨基酸取代专性甘氨酸，这种突变发生在每3个残基中。这些突变的表型效应通常部分归因于三螺旋结构的稳定性和折叠速率的改变。为了更好地理解甘氨酸取代与稳定性之间的关系，我们回顾了目前控制三螺旋稳定性，变性和预变性展开的力的概念，以及测量稳定性的技术。根据对几种胶原蛋白类型以及合成的三肽的稳定性观察，我们提出了一个基于个体和邻近三肽单元对局部稳定性的贡献的稳定性模型。虽然是初步的形式，但这个经验模型可以解释所描述的许多点突变的T(m)的观察位移。回顾了三螺旋结构的折叠。通过环孢素a对成纤维细胞胶原折叠的抑制，证明了肽基脯氨酸顺式反式异构酶在体内参与了这一过程，并提出了基于突变位点热稳定性与折叠再生倾向之间关系的假设。
Osteogenesis imperfecta (OI) is an inherited disease in which 90% of the cases result from mutations in the 2 genes, proalpha1 and proalpha2, coding for type I collagen. Type I collagen is a trimeric molecule, (alpha1)2alpha2, which is dominated both structurally and functionally by the 300 nm triple-helical domain. Most 01 mutations occur in this domain and almost all point mutations result in the substitution of other amino acids for the obligate glycine which occurs at every third residue. The phenotypic effects of these mutations are frequently attributed in part to alterations in the stability and rate of folding of the triple helix. In order to better understand the relationship between glycine substitutions and stability we review current concepts of the forces governing triple helical stability, denaturational and predenaturational unfolding, and the techniques of measuring stability. From observations on the stability of several collagen types as well as synthetic tripeptides, we present a model for stability based on the contribution of individual and neighboring tripeptide units to the local stability. Although in preliminary form, this empirical model can account for the observed shifts in the T(m) of many of the point mutations described. The folding of the triple helix is reviewed. The involvement of peptidyl prolyl cis-trans isomerase in this process in vivo is demonstrated by the inhibition of collagen folding in fibroblasts by cyclosporin A. An hypothesis based on the relationship between the thermal stability at the site of mutation and the propensity for renucleation of folding is proposed.