TY - JOUR
T1 - Comparative analysis of FKBP family protein
T2 - Evaluation, structure, and function in mammals and Drosophila melanogaster
AU - Ghartey-Kwansah, George
AU - Li, Zhongguang
AU - Feng, Rui
AU - Wang, Liyang
AU - Zhou, Xin
AU - Chen, Frederic Z.
AU - Xu, Meng Meng
AU - Jones, Odell
AU - Mu, Yulian
AU - Chen, Shawn
AU - Bryant, Joseph
AU - Isaacs, Williams B.
AU - Ma, Jianjie
AU - Xu, Xuehong
N1 - Funding Information:
This work was supported by the National Natural Science Foundation of China (#31371256/31571273/31771277), the Ministry of Science and Technology of China (#2015CB943100), the National Department of Education Central Universities Research Fund (#GK20130100/201701005/ GERP-17-45), US Maryland Stem Cell Research Fund (2009MSCRFE008300), the Foreign Distinguished Scientist Program from the National Department of Education (#MS2014SXSF038), and the Outstanding Doctoral Thesis fund (#X2014YB02/X2015YB05).
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/3/27
Y1 - 2018/3/27
N2 - 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.
AB - 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.
KW - FK506-binding protein
KW - Hsp90
KW - Inositol 1, 4, 5-trisphosphate
KW - Notch
KW - Peptidyl-prolyl isomerase
KW - Phospholipase C
KW - Ryanodine receptor
KW - Tetratricopetide receptor
KW - Transient receptor potential
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U2 - 10.1186/s12861-018-0167-3
DO - 10.1186/s12861-018-0167-3
M3 - Article
C2 - 29587629
AN - SCOPUS:85044518112
SN - 1471-213X
VL - 18
JO - BMC Developmental Biology
JF - BMC Developmental Biology
IS - 1
M1 - 7
ER -