Protein stability and in vivo concentration of missense mutations in phenylalanine hydroxylase.
Protein stability and in vivo concentration of missense mutations in phenylalanine hydroxylase.
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DOI：
10.1002/prot.23159
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发表时间：
2012-01
影响因子：
2.9
通讯作者：
Moult, John
中科院分区：
文献类型：
--
作者：
Shi, Zhen;Sellers, Jenn;Moult, John
关键词：
之前对与单基因疾病有关的错义突变进行的计算分析发现，错义突变影响蛋白质稳定性的比例很高，而不是影响蛋白质结构和功能的其他方面。本研究的目的是将这种破坏稳定性的错义突变的存在与类似体内条件下存在的特定蛋白质的水平联系起来，并测试计算方法的可靠性。将与单基因疾病苯丙酮尿症(PKU)相关的一组苯丙氨酸羟基酶(PAH)错义突变的实验数据与使用SNPs3D电子分析软件包获得的对蛋白质功能的预期影响进行了比较。据预测，高比例的PAH突变会造成不稳定。对于较低的蛋白质水平，预测的稳定性影响与实验证据之间的总体一致性与方法的估计错误率一致。对于这些突变，蛋白质三维结构的不稳定是导致PKU的主要分子机制，并导致体内PAH蛋白浓度的大幅下降。尽管规模有限，但结果支持这样的观点，即不稳定是错义突变导致单基因疾病的最常见机制。反过来，这一结论表明了开发以恢复野生型稳定性为目标的药物的一般治疗策略。
A previous computational analysis of missense mutations linked to monogenic disease found a high proportion of missense mutations affect protein stability, rather than other aspects of protein structure and function. The purpose of the present study is to relate the presence of such stability damaging missense mutations to the levels of a particular protein present under ‘in vivo’ like conditions, and to test the reliability of the computational methods. Experimental data on a set of missense mutations of the enzyme phenylalanine hydroxylase (PAH) associated with the monogenic disease phenylketonuria (PKU) have been compared with the expected in vivo impact on protein function, obtained using SNPs3D, an in silico analysis package. A high proportion of the PAH mutations are predicted to be destabilizing. The overall agreement between predicted stability impact and experimental evidence for lower protein levels is in accordance with the estimated error rates of the methods. For these mutations, destabilization of protein three dimensional structure is the major molecular mechanism leading to PKU, and results in a substantial reduction of in vivo PAH protein concentration. Although of limited scale, the results support the view that destabilization is the most common mechanism by which missense mutations cause monogenic disease. In turn, this conclusion suggests the general therapeutic strategy of developing drugs targeted at restoring wild type stability.
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DOI：
10.1046/j.1432-1327.1998.2570001.x
发表时间：
1998-10-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Bjorgo, E;Knappskog, PM;Flatmark, T
通讯作者：
Flatmark, T
影响因子：
3.8
作者：
Harding, CO;Neff, M;Milstien, S
通讯作者：
Milstien, S
影响因子：
14.9
作者：
Bromberg Y;Rost B
通讯作者：
Rost B
影响因子：
9.8
作者：
Guldberg, P;Rey, F;Güttler, F
通讯作者：
Güttler, F
影响因子：
4.4
作者：
DWORNICZAK, B;GRUDDA, K;HORST, J
通讯作者：
HORST, J