Molecular recruitment as a basis for negative dominant inheritance? propagation of misfolding in oligomers of IMPDH1, the mutated enzyme in the RP10 form of retinitis pigmentosa.
Molecular recruitment as a basis for negative dominant inheritance? propagation of misfolding in oligomers of IMPDH1, the mutated enzyme in the RP10 form of retinitis pigmentosa.
复制标题
分子募集作为负显性遗传的基础？
DOI：
10.1016/j.bbadis.2011.07.006
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
P. Engel
中科院分区：
文献类型：
--
作者：
Xiao;B. Mion;A. Aherne;P. Engel
导致进行性失明的视网膜色素变性在遗传上是不同的。RP10是一种常染色体显性遗传，由肌苷一磷酸脱氢酶1(IMPDH1)基因缺陷引起。重组表达的临床突变体表现出不变的动力学行为。目前尚不清楚为什么据报道DNA结合受损是重要的，以及它如何解释负显性。另一种观点与突变蛋白质聚集的趋势有关。关于负显性，一个关键的问题是，缺陷蛋白是否可以颠覆同一细胞中正常对应蛋白的功能。潜在地，IMPDH1的同源四聚体结构可能提供了一种实现这种效果的工具。我们已经建立了一种可靠的体外可重复折叠重组表达的IMPDH1的方法。临床突变株R224P和D226N均显示折叠受损。对于等摩尔的正常和突变酶的混合物，独立复性可以预测在纯突变和纯正常之间恢复活性。在各种条件下，恢复与突变图形接近，这表明，在杂交四聚体中，突变亚基将其错误构象强加于正常伴侣。观察到的分子募集是等位基因内互补的负对应物，也是通过寡聚结构介导的，多年前Fincham提出了假设。这些发现似乎潜在地解释了负显性遗传。这种解释目前肯定是暂时的，因为视网膜中的主要转录本是一个选择性剪接版本，与我们研究中使用的版本不完全相同。然而，这些结果对于指出一种可能普遍存在的负显性机制具有普遍意义。
Retinitis pigmentosa, causing progressive blindness, is genetically heterogeneous. RP10, due to a defect in inosine monophosphate dehydrogenase 1 (IMPDH1), shows autosomal dominant inheritance. Recombinantly expressed clinical mutants show unaltered kinetic behaviour. It is unclear why reportedly impaired DNA binding is important and how it would explain negative dominance. An alternative view relates to the mutant proteins' tendency to aggregate. Regarding negative dominance, a key question is whether the defective protein can subvert the function of its normal counterpart in the same cell. Potentially, the homotetrameric structure of IMPDH1 might offer a vehicle for such an effect. We have established a reliable protocol for reproducible refolding of recombinantly expressed IMPDH1 in vitro. Clinical mutants R224P and D226N both show impaired folding. For equimolar mixtures of normal and mutant enzymes, independent refolding would predict activity regain midway between pure mutant and pure normal. Under various conditions regain is close to the mutant figure, suggesting that, in hybrid tetramers, mutant subunits impose their faulty conformation on normal partners. The observed molecular recruitment is a negative counterpart of the intra-allelic complementation, also mediated via oligomeric structure and postulated many years ago by Fincham. These findings appear potentially to account for the negative dominant inheritance. This interpretation must be provisional at present, as the predominant transcript in retina is an alternatively spliced version not fully identical to that used in our study. The results nevertheless have a general significance in pointing to a mechanism for negative dominance that could be widespread.
影响因子：
3.5
作者：
Bowne, SJ;Sullivan, LS;Daiger, SP
通讯作者：
Daiger, SP
影响因子：
4.4
作者：
Wada, Y;Sandberg, MA;Dryja, TP
通讯作者：
Dryja, TP