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

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.

γ-Synuclein confers both pro-invasive and doxorubicin-mediated pro-apoptotic properties to the colon adenocarcinoma LS 174T cell line

“…Interaction of actin filaments with microtubules and intermediate filaments is also evidenced during invadopodia extension [28]. A recent molecular simulation study found that a strong interaction exists between γ-synuclein and the tail regions of microtubule subunits, thereby altering the binding site of microtubuletargeting drug like Taxol and thus causes drug resistance in cancer cells [29]. Members of small GTPases of the Rho family were reported to be able to signal the formation of lamellipodia and filopodia [30].…”

Tracking the Amide I and αCOO− Terminal ν(C=O) Raman Bands in a Family of l-Glutamic Acid-Containing Peptide Fragments: A Raman and DFT Study

“…For example, the E-hook of β-tubulin is instrumental in cytoskeletal regulation and function. The last six C-terminal residues of the βII isotype, amino acid sequence EGEDEA, protrude from the microtubule surface and facilitate protein binding and molecular motor motility [ 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 ]. Unlike investigations by Bour and Reiher, which investigate ordered peptide chains falling into the classic α-helical and β-sheet secondary structure domains [ 28 , 44 , 45 , 46 , 48 , 49 , 85 , 86 , 87 ], EGEDEA is thought to be an intrinsically disordered protein, in part due to the inability to resolve a crystal structure.…”

Mobility and Core-Protein Binding Patterns of Disordered C-Terminal Tails in β-Tubulin Isotypes

“…29 Subsequently, Freedman et al used molecular dynamics to predict the interaction of the C-terminal tails with the tubulin heterodimer in the case of the human αIV-βI isotype. 30 Two additional studies explicitly model the CTTs while investigating the interaction of tubulin with proteins like γ-synuclein 31 or kinesin, 32 which bind the tubulin surface in the vicinity of the CTTs.…”