Open Access

Molecular dynamics simulations of human E3 ubiquitin ligase Parkin

  • Authors:
    • Shi Qiu
    • Shun Zhu
    • Shan Xu
    • Yanyan Han
    • Wen Liu
    • Ji Zuo
  • View Affiliations

  • Published online on: August 2, 2017     https://doi.org/10.3892/mmr.2017.7140
  • Pages: 4561-4568
  • Copyright: © Qiu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Human E3 ubiquitin protein ligase parkin (Parkin) mediates mitophagy to maintain mitochondrial homeostasis. Parkin mutations are common genetic causes of early onset familial Parkinson's disease. The molecular mechanism of Parkin activation has been widely studied with emerging evidence suggesting an essential role of the phosphorylated (phospho)‑ubiquitin interaction. However, the underlying mecha­nism of the phospho‑ubiquitin interaction remains elusive. In the present study, replica exchange molecular dynamics simulations were performed to examine the conformational dynamics of Parkin in monomer and phospho‑ubiquitin‑bound states. In the Parkin monomer state, high structural flexi­bilities were observed in the majority of regions of Parkin particularly in the loop domain between the ubiquitin‑like (UBL) and really interesting new gene (RING)0 domain. Binding of phospho‑ubiquitin stabilizes the RING1/RING in between RING interface but destabilizes the RING1‑UBL interface. Furthermore, using steered molecular dynamics simulations of Parkin mutations, it was demonstrated that salt bridge interactions contribute significantly to the interdomain interactions between the RING1 and UBL domain. Taken together, the results of the present study revealed the conformational dynamics of human full‑length Parkin in monomer and phospho‑ubiquitin‑bound states, providing insights into designing potential therapeutics against Parkinson's disease.

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October-2017
Volume 16 Issue 4

Print ISSN: 1791-2997
Online ISSN:1791-3004

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Spandidos Publications style
Qiu S, Zhu S, Xu S, Han Y, Liu W and Zuo J: Molecular dynamics simulations of human E3 ubiquitin ligase Parkin. Mol Med Rep 16: 4561-4568, 2017
APA
Qiu, S., Zhu, S., Xu, S., Han, Y., Liu, W., & Zuo, J. (2017). Molecular dynamics simulations of human E3 ubiquitin ligase Parkin. Molecular Medicine Reports, 16, 4561-4568. https://doi.org/10.3892/mmr.2017.7140
MLA
Qiu, S., Zhu, S., Xu, S., Han, Y., Liu, W., Zuo, J."Molecular dynamics simulations of human E3 ubiquitin ligase Parkin". Molecular Medicine Reports 16.4 (2017): 4561-4568.
Chicago
Qiu, S., Zhu, S., Xu, S., Han, Y., Liu, W., Zuo, J."Molecular dynamics simulations of human E3 ubiquitin ligase Parkin". Molecular Medicine Reports 16, no. 4 (2017): 4561-4568. https://doi.org/10.3892/mmr.2017.7140