From Drosophila to humans: reflections on the roles of the prolyl isomerases and chaperones, cyclophilins, in cell function and disease.
From Drosophila to humans: reflections on the roles of the prolyl isomerases and chaperones, cyclophilins, in cell function and disease.
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DOI：
10.3109/01677063.2011.647143
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发表时间：
2012-06
影响因子：
1.9
通讯作者：
Orry A
中科院分区：
文献类型：
--
作者：
Ferreira PA;Orry A
尽管人类遗传学和其他遗传模型系统取得了显着的进步，果蝇，黑腹果蝇，仍然是一个强大的实验工具，可以轻松地探索无数生物和病理过程的内部运作，即使进化的力量赋予这些过程明显的分歧。这种进化差异的理解提供了机制的见解基因型-表型的相关性支持跨后生动物的生物过程。过去四十年来，William Pak实验室的开创性工作以及其他人的工作，集中体现了果蝇系统如何开辟新的肥沃土壤或补充具有高度科学和医学相关性的研究领域的概念。在Pak实验室产生的三个主要的遗传互补组中，nina组（ninaA....J）选择性地影响G蛋白偶联受体（GPCR）的生物发生，介导光转换和光刺激的转导。在已鉴定的nina基因中，ninaA可以说具有高度的重要性，原因有几个。首先，它对GPCR的一个子集的生物发生具有独特的生理选择性，这是NinaA的大多数哺乳动物同源物尚未发现的独立生物学表现。其次，NinaA属于蛋白质家族，亲免素，其是在多种医学病症的治疗前沿的免疫抑制药物的主要靶标。第三，NinaA最接近的同源物亲环素-B（CyPB/PPIB）是一种亲免疫素，其功能丧失最近被发现在人类中引起骨生成障碍。本报告重点介绍了一些成员的亲免疫素，亲环素的研究取得的进展。最后，它重新审视了来自NinaA和其他一些亲环素的过去和最近的遗传，结构，生物学和病理学研究的数据和教条，这些研究支持一些这样的范式不太确定，并促进了我们对亲环素在细胞功能，疾病和治疗干预中的作用的理解。
Despite remarkable advances in human genetics and other genetic model systems, the fruit fly, Drosophila melanogaster, remains a powerful experimental tool to probe with ease the inner workings of a myriad of biological and pathological processes, even when evolutionary forces impart apparent divergences to some of such processes. The understanding of such evolutionary differences provides mechanistic insights into genotype-phenotype correlations underpinning biological processes across metazoans. The pioneering work developed by the William Pak laboratory for the past four decades, and the work of others, epitomize the notion of how the Drosophila system breaks new fertile ground or complements research fields of high scientific and medical relevance. Among the three major genetic complementation groups produced by the Pak's laboratory and impairing distinct facets of photoreceptor neuronal function, the nina group (ninaA….J) selectively affects the biogenesis of G protein-coupled receptors (GPCR) mediating the photoconversion and transduction of light-stimuli. Among the nina genes identified, ninaA arguably assumes heightened significance for several reasons. First, it presents unique physiological selectivity toward the biogenesis of a subset of GPCRs, a standalone biological manifestation yet to be discerned for most mammalian homologues of NinaA. Second, NinaA belongs to a family of proteins, immunophilins, which are the primary targets for immunosuppressive drugs at the therapeutic forefront of a multitude of medical conditions. Third, NinaA closest homologue, cyclophilin-B (CyPB/PPIB), is an immunophilin whose loss-of-function was found recently to cause osteogenesis imperfecta in the human. This report highlights advances made by studies on some members of immunophilins, the cyclophilins. Finally, it re-examines critically data and dogmas derived from past and recent genetic, structural, biological and pathological studies on NinaA and few other cyclophilins that support some of such paradigms to be less than definite and advance our understanding of cyclophilins' roles in cell function, disease and therapeutic interventions.