Cyclophilin40 isomerase activity is regulated by a temperature-dependent allosteric interaction with Hsp90

Bioscience Reports
Elizabeth A BlackburnMalcolm D Walkinshaw

Abstract

Cyclophilin 40 (Cyp40) comprises an N-terminal cyclophilin domain with peptidyl-prolyl isomerase (PPIase) activity and a C-terminal tetratricopeptide repeat (TPR) domain that binds to the C-terminal-EEVD sequence common to both heat shock protein 70 (Hsp70) and Hsp90. We show in the present study that binding of peptides containing the MEEVD motif reduces the PPIase activity by ∼30%. CD and fluorescence assays show that the TPR domain is less stable than the cyclophilin domain and is stabilized by peptide binding. Isothermal titration calorimetry (ITC) shows that the affinity for the-MEEVD peptide is temperature sensitive in the physiological temperature range. Results from these biophysical studies fit with the MD simulations of the apo and holo (peptide-bound) structures which show a significant reduction in root mean square (RMS) fluctuation in both TPR and cyclophilin domains when-MEEVD is bound. The MD simulations of the apo-protein also highlight strong anti-correlated motions between residues around the PPIase-active site and a band of residues running across four of the seven helices in the TPR domain. Peptide binding leads to a distortion in the shape of the active site and a significant reduction in these strongly ant...Continue Reading

References

Sep 1, 1975·Proceedings of the National Academy of Sciences of the United States of America·M R Eftink, C A Ghiron
Nov 15, 1990·Analytical Biochemistry·I H van StokkumF C Groen
Jan 6, 1981·Biochemistry·S W Provencher, J Glöckner
Nov 1, 1993·Protein Science : a Publication of the Protein Society·C A RoyerC R Matthews
Jul 11, 1998·The Journal of Biological Chemistry·J C YoungF U Hartl
Jul 23, 2003·Current Topics in Medicinal Chemistry·Jacqueline DornanMalcolm D Walkinshaw
Aug 11, 2004·Analytical Biochemistry·Mei-Chu LoGeorge Ellestad
Feb 17, 2005·Journal of Molecular Biology·Matthew J CliffJohn E Ladbury
Aug 17, 2005·Analytical Biochemistry·Martin A WearMalcolm D Walkinshaw
Oct 14, 2005·Journal of Computational Chemistry·James C PhillipsKlaus Schulten
Nov 4, 2005·Nature·Elan Z EisenmesserDorothee Kern
Mar 24, 2007·The Journal of Biological Chemistry·Frank EdlichGunter Fischer
May 9, 2008·Nucleic Acids Research·Christian ColeGeoffrey J Barton
May 20, 2008·Journal of Molecular Biology·S C OnuohaS E Jackson
May 13, 2009·The International Journal of Biochemistry & Cell Biology·Thomas RatajczakRudi K Allan
Jun 2, 2009·Biochemistry·Sebastian DaumCordelia Schiene-Fischer
Aug 15, 2009·Structure·Antonio del SolRuth Nussinov
Mar 3, 2010·Annual Review of Biophysics·Ivet BaharEran Eyal
Nov 17, 2011·PLoS Biology·Arvind Ramanathan, Pratul K Agarwal
Mar 28, 2012·Proceedings of the National Academy of Sciences of the United States of America·Urmi DoshiDonald Hamelberg
Sep 12, 2013·Biochemistry·Kimberly A WilsonJeffrey W Peng
Nov 2, 2013·Cell Death & Disease·P NigroM C Capogrossi
Dec 30, 2014·Structure·Jingjing GuoHuan-Xiang Zhou

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Citations

Jun 28, 2017·PLoS Biology·Jeremy D BakerLaura J Blair
Jan 10, 2018·Frontiers in Neuroscience·Lindsey B SheltonLaura J Blair
Nov 17, 2020·Frontiers in Plant Science·Harpreet SinghPrabhjeet Singh

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Methods Mentioned

BETA
protein folding
X-ray
thermal
gel filtration
dynamic

Software Mentioned

CONTIN
NAMD
MicroCal ORIGIN
MEEVD
SELCON3

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