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

Abstract

BackgroundFK506-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 bodyThis 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.ConclusionThis 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.

FKBP4 is a malignant indicator in luminal A subtype of breast cancer

“…FK506-binding protein (FKBP) family in Homo sapiens (human) genomes has included 18 FKBPs up to date, which can target on various pathways in embryonic development, stress response, cardiac function, cancer tumorigenesis and neuronal function [15]. In breast cancer, FKBP5 is the most extensively studied protein among identified human FKBPs, which is demonstrated to interact with HSP90 to affect steroid hormone receptor function [16].…”

Tacrolimus treatment for infertility related to maternal‐fetal immune interactions

“…Elucidation of the detailed mechanisms of signal transduction in cells has led to the successful use of tacrolimus in the fields of transplantation andautoimmune disease . Tacrolimus has been reported to act not only via the CN‐NFAT pathway in T cells, but also in other cell types, including NK/NKT cells, macrophages, B cells, and DC cells . Direct inhibition occurs in T cells, NK/NKT cells, and macrophages.…”

“…Interestingly, many FKBP family members have been identified in cells. Although the functions of some proteins have not yet been elucidated, proteins influenced by tacrolimus (FK506) are thought to affect several cellular and molecular pathways and to be associated with different physiological functions . Several FKBPs have also been implicated in hormonal pathways.…”

FKBP9 promotes the malignant behavior of glioblastoma cells and confers resistance to endoplasmic reticulum stress inducers

“…Background FK506-binding protein 9 (FKBP9) belongs to a family of immunophilins that are able to bind to FK506, an immunosuppressive drug [1]. FKBPs are known to be involved in multiple biological processes, such as playing its immunosuppressive roles and inactivating the nuclear factor of activated T-cells [1,2]. In addition, FKBPs have been implicated in cancer development.…”