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A hidden aggregation-prone structure in the heart of hypoxia inducible factor prolyl hydroxylase

Hamid Hadi-Alijanvand1,2, Elizabeth A Proctor3, Feng Ding4,5

  • 1Department of Biological Sciences, Institute for Advanced Studies in Basic Sciences (IASBS), Zanjan, Iran.

Proteins
|February 13, 2016
PubMed

Insights

Prolyl hydroxylase domain-containing protein 2 (PHD2) unfolding was studied to understand cancer. An intermediate species was found, explaining PHD2 malfunction independent of mutations.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Prolyl hydroxylase domain-containing protein 2 (PHD2) is crucial in regulating cancer angiogenesis and metastasis.
  • PHD2 dysfunction, potentially due to misfolding, is implicated in cancer development.
  • Understanding PHD2's protein folding pathway is vital for cancer therapy drug design.

Purpose of the Study:

  • To investigate the thermal unfolding pathway of the PHD2 catalytic domain.
  • To elucidate the atomic-level events during PHD2 unfolding.
  • To understand how mutations and metabolites affect PHD2 folding.

Main Methods:

  • Differential Scanning Calorimetry (DSC) for thermal unfolding.
  • Fluorescence spectroscopy for structural changes.
  • Discrete Molecular Dynamics (DMD) simulations for atomic detail.

Main Results:

  • PHD2 exhibits four distinct transitions during thermal unfolding.
  • DMD simulations revealed an intermediate species in the unfolding pathway.
  • This intermediate may increase protein aggregation, leading to malfunction.

Conclusions:

  • PHD2 unfolding is a complex process with identifiable intermediate states.
  • The identified intermediate species offers a potential explanation for mutation-independent PHD2 malfunction in cancer.
  • Targeting PHD2 folding pathways could be a novel therapeutic strategy for cancer.
Keywords:
HIF-1aggregation prone intermediate stateangiogenesiscalorimetrydiscrete molecular dynamicspotential of mean forceprotein misfolding

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