BACKGROUND FK506-binding proteins (FKBPs) have become the subject of considerable interest in several fields, leading to the identification of several cellular and molecular pathways in which FKBPs impact prenatal development and pathogenesis of many human diseases. MAIN BODY This analysis revealed differences between how mammalian and Drosophila FKBPs mechanisms function in relation to the immunosuppressant drugs, FK506 and rapamycin. Differences that could be used to design insect-specific pesticides. (1) Molecular phylogenetic analysis of FKBP family proteins revealed that the eight known Drosophila FKBPs share homology with the human FKBP12. This indicates a close evolutionary relationship, and possible origination from a common ancestor. (2) The known FKBPs contain FK domains, that is, a prolyl cis/trans isomerase (PPIase) domain that mediates immune suppression through inhibition of calcineurin. The dFKBP59, CG4735/Shutdown, CG1847, and CG5482 have a Tetratricopeptide receptor domain at the C-terminus, which regulates transcription and protein transportation. (3) FKBP51 and FKBP52 (dFKBP59), along with Cyclophilin 40 and protein phosphatase 5, function as Hsp90 immunophilin co-chaperones within steroid receptor-Hsp90 heterocomplexes. These immunophilins are potential drug targets in pathways associated with normal physiology and may be used to treat a variety of steroid-based diseases by targeting exocytic/endocytic cycling and vesicular trafficking. (4) By associating with presinilin, a critical component of the Notch signaling pathway, FKBP14 is a downstream effector of Notch activation at the membrane. Meanwhile, Shutdown associates with transposons in the PIWI-interacting RNA pathway, playing a crucial role in both germ cells and ovarian somas. Mutations in or silencing of dFKBPs lead to early embryonic lethality in Drosophila. Therefore, further understanding the mechanisms of FK506 and rapamycin binding to immunophilin FKBPs in endocrine, cardiovascular, and neurological function in both mammals and Drosophila would provide prospects in generating unique, insect specific therapeutics targeting the above cellular signaling pathways. CONCLUSION This review will evaluate the functional roles of FKBP family proteins, and systematically summarize the similarities and differences between FKBP proteins in Drosophila and Mammals. Specific therapeutics targeting cellular signaling pathways will also be discussed.

中文翻译：

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FKBP家族蛋白的比较分析：在哺乳动物和果蝇中的评估，结构和功能。

背景技术FK506结合蛋白（FKBP）已经在几个领域中引起了广泛的关注，导致鉴定了其中FKBP影响许多人类疾病的产前发育和发病机理的几种细胞和分子途径。主要身体该分析揭示了哺乳动物和果蝇FKBPs机制在免疫抑制剂，FK506和雷帕霉素方面的功能差异。可用于设计昆虫特异性农药的差异。（1）对FKBP家族蛋白的分子系统发育分析表明，八个已知的果蝇FKBP与人FKBP12具有同源性。这表明了密切的进化关系，并且可能起源于一个共同的祖先。（2）已知的FKBP包含FK域，即 一个脯氨酰顺/反异构酶（PPIase）域，通过抑制钙调神经磷酸酶介导免疫抑制。dFKBP59，CG4735 / Shutdown，CG1847和CG5482在C端具有四肽肽受体域，该域调节转录和蛋白质运输。（3）FKBP51和FKBP52（dFKBP59），以及亲环蛋白40和蛋白磷酸酶5，在类固醇受体-Hsp90杂合物中充当Hsp90亲免蛋白伴侣分子。这些亲免蛋白是与正常生理相关的途径中的潜在药物靶标，可通过靶向胞外/内循环和囊泡运输而用于治疗多种基于类固醇的疾病。（4）通过与Presinilin（Notch信号通路的关键组成部分）相关联，FKBP14是膜上Notch激活的下游效应子。与此同时，关机在PIWI相互作用的RNA途径中与转座子相关联，在生殖细胞和卵巢体中均起着至关重要的作用。dFKBPs突变或沉默导致果蝇早期胚胎致死。因此，进一步了解FK506和雷帕霉素在哺乳动物和果蝇的内分泌，心血管和神经功能中与亲免蛋白FKBPs结合的机制将为产生针对上述细胞信号通路的独特昆虫特异性疗法提供前景。结论本综述将评估FKBP家族蛋白的功能作用，并系统地总结果蝇和哺乳动物中FKBP蛋白之间的异同。还讨论了靶向细胞信号传导途径的特定疗法。