Unfolding mechanism of PHD2 as a vital protein: all-atom simulation approach
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Prolyl hydroxylase domain 2 containing protein (PHD2) is a central protein in regulation of cellular response to hypoxia. This protein controls the responses of cell to oxygen level via the regulation of hypoxia inducible factor (HIF) stability. HIF induces the expression of many genes, especially ones orchestrate angiogenesis. There are some reports that mentioned in some tumor types the level of HIF is high in spite of the presence of wild-type PHD2 and normoxic environment. Therefore, the possibility of PHD2 misfolding in some cancer cells arises. Studying such important protein unfolding pathway is insightful for possible therapeutic approaches. In this study, the unfolding pathway of PHD2 illustrates utilizing molecular dynamics simulation of protein thermal denaturation. Based on current study results, we represent the possible mechanisms of PHD2 unfolding in detail. The possible intermediates of PHD2 thermal unfolding are characterized, and the most venomous state of its unfolding pathway is introduced.
KeywordsPHD2 Angiogenesis Protein unfolding pathway Molecular dynamics simulation Intermediate states Unfolding mechanism
We gratefully acknowledge the support of the University of Tehran, Iran National Science Foundation (INSF), and the Center of Excellence in Biothermodynamics (CEBiotherm).
- 13.H. Zhong, A.M. De Marzo, E. Laughner, M. Lim, D.A. Hilton, D. Zagzag, P. Buechler, W.B. Isaacs, G.L. Semenza, J.W. Simons, Cancer Res. 59, 5830–5835 (1999)Google Scholar
- 18.V. Daggett, Methods Mol. Biol. 168, 215–247 (2001)Google Scholar
- 28.W. Humphrey, A. Dalke, K. Schulten, J. Mol. Graph. 14(33–38), 27–38 (1996)Google Scholar
- 33.S.J. Sheather, C. Jones, J. R. Stat. Soc: Ser. B (Stat. Methodol.) 53, 683–690 (1991)Google Scholar
- 34.T.F. Cox, M.A.A. Cox, Multidimensional scaling (Chapman & Hall, London, 1994)Google Scholar