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Tytuł pozycji:

FKBP12 dimerization mutations effect FK506 binding and differentially alter calcineurin inhibition in the human pathogen Aspergillus fumigatus.

Tytuł:
FKBP12 dimerization mutations effect FK506 binding and differentially alter calcineurin inhibition in the human pathogen Aspergillus fumigatus.
Autorzy:
Juvvadi PR; Division of Pediatric Infectious Diseases, Department of Pediatrics, Duke University Medical Center, Durham, NC, 27710, USA. Electronic address: .
Bobay BG; Duke University NMR Center, Duke University Medical Center, Durham, NC, 27710, USA; Department of Biochemistry, Durham, NC, 27710, USA; Department of Radiology, Duke University, Durham, NC, 27710, USA.
Gobeil SMC; Department of Biochemistry, Durham, NC, 27710, USA; Department of Radiology, Duke University, Durham, NC, 27710, USA.
Cole DC; Division of Pediatric Infectious Diseases, Department of Pediatrics, Duke University Medical Center, Durham, NC, 27710, USA.
Venters RA; Duke University NMR Center, Duke University Medical Center, Durham, NC, 27710, USA; Department of Biochemistry, Durham, NC, 27710, USA; Department of Radiology, Duke University, Durham, NC, 27710, USA.
Heitman J; Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, 27710, USA.
Spicer LD; Duke University NMR Center, Duke University Medical Center, Durham, NC, 27710, USA; Department of Biochemistry, Durham, NC, 27710, USA; Department of Radiology, Duke University, Durham, NC, 27710, USA.
Steinbach WJ; Division of Pediatric Infectious Diseases, Department of Pediatrics, Duke University Medical Center, Durham, NC, 27710, USA; Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, 27710, USA. Electronic address: .
Źródło:
Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2020 May 21; Vol. 526 (1), pp. 48-54. Date of Electronic Publication: 2020 Mar 16.
Typ publikacji:
Journal Article; Research Support, N.I.H., Extramural
Język:
English
Imprint Name(s):
Publication: <2002- >: San Diego, CA : Elsevier
Original Publication: New York, Academic Press.
MeSH Terms:
Protein Multimerization*
Aspergillus fumigatus/*metabolism
Calcineurin/*metabolism
Calcineurin Inhibitors/*pharmacology
Fungal Proteins/*genetics
Mutation/*genetics
Tacrolimus/*pharmacology
Tacrolimus Binding Protein 1A/*genetics
Amino Acid Sequence ; Computer Simulation ; Fungal Proteins/chemistry ; Fungal Proteins/metabolism ; Humans ; Mutant Proteins/chemistry ; Mutant Proteins/metabolism ; Protein Binding/drug effects ; Protein Structure, Secondary ; Tacrolimus Binding Protein 1A/chemistry ; Tacrolimus Binding Protein 1A/metabolism
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Grant Information:
P01 AI104533 United States AI NIAID NIH HHS; R01 AI112595 United States AI NIAID NIH HHS; R56 AI112595 United States AI NIAID NIH HHS; R56 AI123502 United States AI NIAID NIH HHS
Contributed Indexing:
Keywords: Aspergillus; Calcineurin; Dimerization; FK506; FKBP12; Molecular dynamics
Substance Nomenclature:
0 (Calcineurin Inhibitors)
0 (Fungal Proteins)
0 (Mutant Proteins)
EC 3.1.3.16 (Calcineurin)
EC 5.2.1.- (Tacrolimus Binding Protein 1A)
WM0HAQ4WNM (Tacrolimus)
Entry Date(s):
Date Created: 20200321 Date Completed: 20201124 Latest Revision: 20221116
Update Code:
20240105
PubMed Central ID:
PMC7188580
DOI:
10.1016/j.bbrc.2020.03.062
PMID:
32192767
Czasopismo naukowe
The 12-kDa FK506-binding protein (FKBP12) is the target of the commonly used immunosuppressive drug FK506. The FKBP12-FK506 complex binds to calcineurin and inhibits its activity, leading to immunosuppression and preventing organ transplant rejection. Our recent characterization of crystal structures of FKBP12 proteins in pathogenic fungi revealed the involvement of the 80's loop residue (Pro90) in the active site pocket in self-substrate interaction providing novel evidence on FKBP12 dimerization in vivo. The 40's loop residues have also been shown to be involved in reversible dimerization of FKBP12 in the mammalian and yeast systems. To understand how FKBP12 dimerization affects FK506 binding and influences calcineurin function, we generated Aspergillus fumigatus FKBP12 mutations in the 40's and 50's loop (F37 M/L; W60V). Interestingly, the mutants exhibited variable FK506 susceptibility in vivo indicating differing dimer strengths. In comparison to the 80's loop P90G and V91C mutants, the F37 M/L and W60V mutants exhibited greater FK506 resistance, with the F37M mutation showing complete loss in calcineurin binding in vivo. Molecular dynamics and pulling simulations for each dimeric FKBP12 protein revealed a two-fold increase in dimer strength and significantly higher number of contacts for the F37M, F37L, and W60V mutations, further confirming their varying degree of impact on FK506 binding and calcineurin inhibition in vivo.
Competing Interests: Declaration of competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2020 Elsevier Inc. All rights reserved.)

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