Collagen Gly missense mutations: Effect of residue identity on collagen structure and integrin binding.
Collagen Gly missense mutations: Effect of residue identity on collagen structure and integrin binding.
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DOI：
10.1016/j.jsb.2018.05.003
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发表时间：
2018-09
影响因子：
3
通讯作者：
Brodsky B
中科院分区：
文献类型：
--
作者：
Qiu Y;Mekkat A;Yu H;Yigit S;Hamaia S;Farndale RW;Kaplan DL;Lin YS;Brodsky B
已知I型胶原中的Gly错义突变，其用较大残基替换重复（Gly-Xaa-Yaa）n序列中的保守Gly，导致成骨不全（OI）。这种突变的临床后果范围从轻度到致死，更严重的临床严重程度与较大的Gly替代残基相关。在这里，我们调查的身份的残基取代甘氨酸内和附近的整合素结合502 GFPGER 507序列的三螺旋结构，稳定性和整合素结合使用重组细菌胶原蛋白系统的影响。在整合素结合区内的四个位置用Ala、Ser或瓦尔取代Gly构建重组胶原。所有构建体均形成稳定的三螺旋结构，其中解链温度略有降低。胰蛋白酶用于探测三螺旋的局部破坏，并且Gly到瓦尔的替换使得三螺旋胰蛋白酶在四个位点中的三个敏感。Gly 505处的任何突变消除了整联蛋白结合，而在Gly 502处的Gly残基的替换中观察到整联蛋白结合亲和力降低，顺序为瓦尔> Ser > Ala。分子动力学模拟表明，所有的Gly替换导致三螺旋链间氢键的Gly替换的区域中的瞬时中断。这些计算和实验结果有助于深入了解OI不同临床严重程度的复杂分子基础。
Gly missense mutations in type I collagen, which replace a conserved Gly in the repeating (Gly-Xaa-Yaa)n sequence with a larger residue, are known to cause Osteogenesis Imperfecta (OI). The clinical consequences of such mutations range from mild to lethal, with more serious clinical severity associated with larger Gly replacement residues. Here, we investigate the influence of the identity of the residue replacing Gly within and adjacent to the integrin binding 502GFPGER507 sequence on triple-helix structure, stability and integrin binding using a recombinant bacterial collagen system. Recombinant collagens were constructed with Gly substituted by Ala, Ser or Val at four positions within the integrin binding region. All constructs formed a stable triple-helix structure with a small decrease in melting temperature. Trypsin was used to probe local disruption of the triple helix, and Gly to Val replacements made the triple helix trypsin sensitive at three of the four sites. Any mutation at Gly505, eliminated integrin binding, while decreased integrin binding affinity was observed in the replacement of Gly residues at Gly502 following the order Val > Ser > Ala. Molecular dynamics simulations indicated that all Gly replacements led to transient disruption of triple-helix interchain hydrogen bonds in the region of the Gly replacement. These computational and experimental results lend insight into the complex molecular basis of the varying clinical severity of OI.
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