Journal
JOURNAL OF CHEMICAL PHYSICS
Volume 148, Issue 14, Pages -Publisher
AMER INST PHYSICS
DOI: 10.1063/1.5019457
Keywords
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Funding
- Istanbul Technical University Scientific Research Projects (BAP) Unit [MGA-2018-41072]
- British Council UK-Turkey Partnership Programme [TR/012012/KP01]
- Edinburgh University Protein Production Facility (EPPF)
- Wellcome Trust [101527/Z/13/Z]
- Wellcome Trust [101527/Z/13/Z] Funding Source: Wellcome Trust
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Cyclophilin 40 (Cyp40) is a member of the immunophilin family that acts as a peptidyl-prolyl-isomerase enzyme and binds to the heat shock protein 90 (Hsp90). Its structure comprises an N-terminal cyclophilin domain and a C-terminal tetratricopeptide (TPR) domain. Cyp40 is over-expressed in prostate cancer and certain T-cell lymphomas. The groove for Hsp90 binding on the TPR domain includes residues Lys227 and Lys308, referred to as the carboxylate clamp, and is essential for Cyp40-Hsp90 binding. In this study, the effect of two mutations, K227A and K308A, and their combinative mutant was investigated by performing a total of 5.76 mu s of all-atom molecular dynamics (MD) simulations in explicit solvent. All simulations, except the K308A mutant, were found to adopt two distinct (extended or compact) conformers defined by different cyclophilin-TPR interdomain distances. The K308A mutant was only observed in the extended form which is observed in the Cyp40 X-ray structure. The wild-type, K227A, and combined mutant also showed bimodal distributions. The experimental melting temperature, T-m, values of the mutants correlate with the degree of compactness with the K308A extended mutant having a marginally lower melting temperature. Another novel measure of compactness determined from the MD data, the coordination shell volume, also shows a direct correlation with Tm. In addition, the MD simulations show an allosteric effect with the mutations in the remote TPR domain having a pronounced effect on the molecular motions of the enzymatic cyclophilin domain which helps rationalise the experimentally observed increase in enzyme activity measured for all three mutations. (C) 2018 Author(s).
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