Comparative analysis of FKBP family protein: evaluation, structure, and function in mammals and Drosophila melanogaster

Abstract

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.

Keywords: FK506-binding protein; Hsp90; Inositol 1, 4, 5-trisphosphate; Notch; Peptidyl-prolyl isomerase; Phospholipase C; Ryanodine receptor; Tetratricopetide receptor; Transient receptor potential.

Fig. 1

Molecular phylogenetic analysis of FKBP family proteins by Maximum Likelihood. The evolutionary tree is presented to compare each subgroup with family members present in other species. The evolutionary history was inferred using the Neighbor-Join and BioNJ algorithms. The percentage of replicate trees in which the associated taxa clustered together in the bootstrap test (500 replicates) is shown next to the branches. Evolutionary analyses were conducted in MEGA7. The proteins were analyzed as intact sequences. The analysis involved genes from C. elegans(ce), Schizosaccharomyces pombe (sp), Arabidopsis thaliana (at), Anopheles gambia (ag), Aedes albopictus (aa), Culex quinquefasciatus (cq), Drosophila melanogaster (dm), Mus musculus (mm) and Homo sapiens (hs)

Fig. 2

Multi-alignment analysis of FKBP family proteins. A multiple sequence alignment of domains from (a) overall FKBP family proteins and (b) only the well-established FKBPs of Drosophila melanogaster show relative similarities among FKBP12 paralogues and orthologues at the amino acid level (black). The dotted box in A indicates domains of well-established FKBP proteins among the overall FKBP family proteins

Fig. 3

Summary of FKBPs’ involvement in different biological processes in Mammal and Drosophila. The cellular functions of the various FKBPs listed on the top include receptor signaling, protein folding and trafficking, transcriptional control, and apoptosis. The FKBPs are also associated with different physiological roles within stress response, cardiac function, cancer genesis, neuronal function, and during animal development