A hidden aggregation‐prone structure in the heart of hypoxia inducible factor prolyl hydroxylase |
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| Authors: | Hamid Hadi‐Alijanvand Elizabeth A Proctor Feng Ding Nikolay V Dokholyan Ali A Moosavi‐Movahedi |
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| Affiliation: | 1. Department of Biological Sciences, Institute for Advanced Studies in Basic Sciences (IASBS), Zanjan, Iran;2. Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran;3. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts;4. Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, North Carolina;5. Department of Physics and Astronomy, Clemson University, Clemson, South Carolina;6. Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, North Carolina;7. Program in Molecular and Cellular Biophysics, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, North Carolina;8. Center of Excellence in Biothermodynamics, Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran |
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| Abstract: | 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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| Keywords: | HIF‐1 aggregation prone intermediate state protein misfolding angiogenesis discrete molecular dynamics calorimetry potential of mean force |
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