A hidden aggregation-prone structure in the heart of hypoxia inducible factor prolyl hydroxylase
Hamid Hadi-Alijanvand
Department of Biological Sciences, Institute for Advanced Studies in Basic Sciences (IASBS), Zanjan, Iran
Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran
Search for more papers by this authorElizabeth A. Proctor
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139
Search for more papers by this authorFeng Ding
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, North Carolina, 27599
Department of Physics and Astronomy, Clemson University, Clemson, South Carolina, 29634
Search for more papers by this authorNikolay V. Dokholyan
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, North Carolina, 27599
Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, North Carolina, 27599
Program in Molecular and Cellular Biophysics, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, North Carolina, 27599
Search for more papers by this authorCorresponding Author
Ali A. Moosavi-Movahedi
Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran
Center of Excellence in Biothermodynamics, Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran
Correspondence to: Ali A. Moosavi-Movahedi, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran. E-mail: [email protected]Search for more papers by this authorHamid Hadi-Alijanvand
Department of Biological Sciences, Institute for Advanced Studies in Basic Sciences (IASBS), Zanjan, Iran
Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran
Search for more papers by this authorElizabeth A. Proctor
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139
Search for more papers by this authorFeng Ding
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, North Carolina, 27599
Department of Physics and Astronomy, Clemson University, Clemson, South Carolina, 29634
Search for more papers by this authorNikolay V. Dokholyan
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, North Carolina, 27599
Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, North Carolina, 27599
Program in Molecular and Cellular Biophysics, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, North Carolina, 27599
Search for more papers by this authorCorresponding Author
Ali A. Moosavi-Movahedi
Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran
Center of Excellence in Biothermodynamics, Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran
Correspondence to: Ali A. Moosavi-Movahedi, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran. E-mail: [email protected]Search for more papers by this authorABSTRACT
Prolyl hydroxylase domain-containing protein 2 (PHD2), as one of the most important regulators of angiogenesis and metastasis of cancer cells, is a promising target for cancer therapy drug design. Progressive studies imply that abnormality in PHD2 function may be due to misfolding. Therefore, study of the PHD2 unfolding pathway paves the way for a better understanding of the influence of PHD2 mutations and cancer cell metabolites on the protein folding pathway. We study the unfolding of the PHD2 catalytic domain using differential scanning calorimetry (DSC), fluorescence spectroscopy, and discrete molecular dynamics simulations (DMD). Using computational and experimental techniques, we find that PHD2 undergoes four transitions along the thermal unfolding pathway. To illustrate PHD2 unfolding events in atomic detail, we utilize DMD simulations. Analysis of computational results indicates an intermediate species in the PHD2 unfolding pathway that may enhance aggregation propensity, explaining mutation-independent PHD2 malfunction. Proteins 2016; 84:611–623. © 2016 Wiley Periodicals, Inc.
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