PDF(Pubmed)
Abstract：
Small GTPases are the key to actin cytoskeleton signaling, which opens the lock of effector proteins to forward the signal downstream in several cellular pathways. Actin cytoskeleton assembly is associated with cell polarity, adhesion, movement and other functions in eukaryotic cells. Rho proteins, specifically Cdc42 and Rac, are the primary regulators of actin cytoskeleton dynamics in higher and lower eukaryotes. Effector proteins, present in an inactive state gets activated after binding to the GTP bound Cdc42/Rac to relay a signal downstream. Cdc42/Rac interactive binding (CRIB) motif is an essential conserved sequence found in effector proteins to interact with Cdc42 or Rac. A diverse range of Cdc42/Rac and their effector proteins have evolved from lower to higher eukaryotes. The present study has identified and further classified CRIB containing effector proteins in lower eukaryotes, focusing on parasitic protozoans causing neglected tropical diseases and taking human proteins as a reference point to the highest evolved organism in the evolutionary trait. Lower eukaryotes\' CRIB containing proteins fall into conventional effector molecules, PAKs (p21 activated kinase), Wiskoit-Aldrich Syndrome proteins family, and some have unique domain combinations unlike any known proteins. We also highlight the correlation between the effector protein isoforms and their selective specificity for Cdc42 or Rac proteins during evolution. Here, we report CRIB containing effector proteins; ten in Dictyostelium and Entamoeba, fourteen in Acanthamoeba, one in Trypanosoma and Giardia. CRIB containing effector proteins that have been studied so far in humans are potential candidates for drug targets in cancer, neurological disorders, and others. Conventional CRIB containing proteins from protozoan parasites remain largely elusive and our data provides their identification and classification for further in-depth functional validations. The tropical diseases caused by protozoan parasites lack combinatorial drug targets as effective paradigms. Targeting signaling mechanisms operative in these pathogens can provide greater molecules in combatting their infections.
摘要：
小GTP酶是肌动蛋白细胞骨架信号的关键，这打开了效应蛋白的锁，以在几种细胞途径的下游转发信号。肌动蛋白细胞骨架组装与细胞极性有关，附着力,真核细胞中的运动和其他功能。Rho蛋白,特别是Cdc42和Rac，是高级和低级真核生物中肌动蛋白细胞骨架动力学的主要调节因子。效应蛋白，在结合到GTP结合的Cdc42/Rac以在下游中继信号之后,存在于非活动状态中被激活。Cdc42/Rac相互作用结合(CRIB)基序是在效应蛋白中发现的与Cdc42或Rac相互作用的必需保守序列。不同范围的Cdc42/Rac及其效应蛋白已经从低级真核生物进化到高级真核生物。本研究已经在低等真核生物中鉴定并进一步分类了含有CRIB的效应蛋白，专注于寄生原生动物导致被忽视的热带疾病，并以人类蛋白质作为进化特征中进化最高的生物的参考点。低等真核生物含有CRIB的蛋白质落入常规效应分子中，PAKs(p21活化激酶),Wiskoit-Aldrich综合征蛋白家族,和一些独特的结构域组合不同于任何已知的蛋白质。我们还强调了效应蛋白同工型之间的相关性及其在进化过程中对Cdc42或Rac蛋白的选择性特异性。这里,我们报告了含有效应蛋白的CRIB；十种在Dictyostelium和Entamoeba中，14个在棘阿米巴，锥虫和贾第虫.到目前为止，已经在人类中研究的含有效应蛋白的CRIB是癌症药物靶标的潜在候选者，神经系统疾病,和其他人。含有来自原生动物寄生虫的蛋白质的常规CRIB在很大程度上仍然难以捉摸，我们的数据为进一步深入的功能验证提供了它们的鉴定和分类。由原生动物寄生虫引起的热带疾病缺乏作为有效范例的组合药物靶标。在这些病原体中起作用的靶向信号机制可以提供更多的分子来对抗它们的感染。
