Hu J, Fei Y, Liu X S, Wang F, Ma D W, Liu S L
School of mechanical engineering, Nanjing University of Science and Technology, Nanjing, P.R. China.
Cell Mol Biol (Noisy-le-grand). 2009 Nov 20;55 Suppl:OL1200-7.
The significance of endothelial P120 catenin (P120ctn) activity has been recognized for many years, however it was only recently that the complicated regulation of this constitutively expressed enzyme in endothelial cells was identified. A critical component of the P120ctn regulatory cycle in endothelial cells is its intracellular localization to caveolae. The caveolar coordination of P120ctn, more specifically its interaction with E-cadherin plays a major role in normal endothelial P120ctn activity and vascular bioavailability of nitric oxide. We have recently shown that the presence of P120ctn exon 7 Phe389Leu polymorphism caused diminished shear which was dependent catenin activation, was less extensively associated with caveolae, and had a decreased degree of interaction with E-cadherin. Here, we carried out preliminary investigations to identify possible mechanisms of the genotype-dependent endothelial cell responses we observed in our previous investigations. Through this approach we tested the hypothesis that computer simulations could provide insights regarding the contribution of this single nucleotide polymorphism to regulation of the P120ctn isoform. We observed that in the Phe/Leu and Leu/Leu mutant genotypes, the amount of P120ctn associated with E-cadherin was significantly lower. Additionally, we have shown, using a theoretical computational model, that mutation of an amino acid at position 389 might affect the protein-protein interactions and localization of the P120ctn protein. These alterations might also affect the protein function and explain the enhanced disease risk associated with the presence of Phe389Leu polymorphism in the P120ctn protein.
多年来，内皮细胞P120连环蛋白（P120ctn）活性的重要性已得到认可，然而直到最近才确定了这种在内皮细胞中组成性表达的酶的复杂调控机制。内皮细胞中P120ctn调控循环的一个关键组成部分是其在小窝中的细胞内定位。P120ctn的小窝协调作用，更具体地说是其与E-钙黏蛋白的相互作用，在正常内皮细胞P120ctn活性和一氧化氮的血管生物利用度中起主要作用。我们最近发现，P120ctn外显子7的Phe389Leu多态性的存在导致剪切力减弱，这依赖于连环蛋白激活，与小窝的关联程度较低，并且与E-钙黏蛋白的相互作用程度降低。在此，我们进行了初步研究，以确定我们在先前研究中观察到的基因型依赖性内皮细胞反应的可能机制。通过这种方法，我们检验了以下假设：计算机模拟可以提供有关这种单核苷酸多态性对P120ctn异构体调控作用的见解。我们观察到，在Phe/Leu和Leu/Leu突变基因型中，与E-钙黏蛋白相关的P120ctn量显著降低。此外，我们使用理论计算模型表明，389位氨基酸的突变可能会影响P120ctn蛋白的蛋白质-蛋白质相互作用和定位。这些改变也可能影响蛋白质功能，并解释了P120ctn蛋白中Phe389Leu多态性的存在与疾病风险增加之间的关联。
