Affordable Access

deepdyve-link
Publisher Website

Molecular dynamic simulations of the tubulin-human gamma synuclein complex: structural insight into the regulatory mechanism involved in inducing resistance against Taxol.

Authors
  • Panneerselvam, Manivel1
  • Muthu, Kannan
  • Jayaraman, Muthukumaran
  • Sridharan, Upasana
  • Jenardhanan, Pranitha
  • Ramadas, Krishna
  • 1 Centre for Bioinformatics, School of Life sciences, Pondicherry University, Puducherry-605 014, India. , (India)
Type
Published Article
Journal
Molecular BioSystems
Publisher
The Royal Society of Chemistry
Publication Date
Jun 01, 2013
Volume
9
Issue
6
Pages
1470–1488
Identifiers
DOI: 10.1039/c3mb25427e
PMID: 23532302
Source
Medline
License
Unknown

Abstract

Members of the synuclein family (α, β and γ synucleins) are intrinsically disordered in nature and play a crucial role in the progression of various neurodegenerative disorders and cancers. The association of γSyn with both BubR1 as well as microtubule subunits renders resistance against various anti-cancer drugs. However, the structural aspects underlying drug resistance have not been explored. In this study, the mechanism involved in the association between γSyn and microtubule subunits (αβTub) was investigated and the results reveal a strong interaction between γSyn and the tail regions of αβTub. Complexation of γSyn induces conformational rearrangements in the nucleotide binding loops (NBL), interdomain and tail regions of both α and βTub. Moreover, in βTub, the massive displacement observed in M and S loops significantly alters the binding site of microtubule targeting drugs like Taxol. The resulting weak association between Taxol and βTub of the γSyn-αβTub complex was confirmed by molecular dynamic simulation studies. In addition, the effect of Taxol on NBL, M and S loops of αβTub, is reversed in the presence of γSyn. These results clearly indicate that the presence of γSyn annulled the allosteric regulation imposed by Taxol on the αβTub complex as well as preventing the binding of microtubule targeting drugs, which eventually leads to the development of resistance against these drugs in cancer cells.

Report this publication

Statistics

Seen <100 times