scispace - formally typeset
Search or ask a question
Author

Jagan Mohan

Bio: Jagan Mohan is an academic researcher from Indian Institute of Technology Madras. The author has contributed to research in topics: Microtubule & Tubulin. The author has an hindex of 1, co-authored 1 publications receiving 11 citations.

Papers
More filters
Journal ArticleDOI
TL;DR: An attempt is made by combining molecular dynamics simulations and protein-protein docking studies that unravels key structural features of tubulin dimer in different nucleotide states and correlates their association to tubulin assembly, providing valuable insights on in vitro finding that GTP-tubulin is a better assembly candidate than GDP- Tubulin during the MT nucleation and elongation processes.
Abstract: The complex dynamic behavior of microtubules (MTs) is believed to be primarily due to the αβ-tubulin dimer architecture and its intrinsic GTPase activity. Hence, a detailed knowledge of the conformational variations of isolated α-GTP-β-GTP- and α-GTP-β-GDP-tubulin dimers in solution and their implications to interdimer interactions and stability is directly relevant to understand the MT dynamics. An attempt has been made here by combining molecular dynamics (MD) simulations and protein-protein docking studies that unravels key structural features of tubulin dimer in different nucleotide states and correlates their association to tubulin assembly. Results from simulations suggest that tubulin dimers and oligomers attain curved conformations in both GTP and GDP states. Results also indicate that the tubulin C-terminal domain and the nucleotide state are closely linked. Protein-protein docking in combination with MD simulations suggest that the GTP-tubulin dimers engage in relatively stronger interdimer interactions even though the interdimer interfaces are bent in both GTP and GDP tubulin complexes, providing valuable insights on in vitro finding that GTP-tubulin is a better assembly candidate than GDP-tubulin during the MT nucleation and elongation processes.

13 citations


Cited by
More filters
Journal ArticleDOI
TL;DR: It is argued that the higher flexibility of the inter-dimer interface may have implications for development of pulling force by curving tubulin protofilaments during microtubule disassembly, a process of major importance for chromosome motions in mitosis.
Abstract: Thirteen tubulin protofilaments, made of αβ-tubulin heterodimers, interact laterally to produce cytoskeletal microtubules. Microtubules exhibit the striking property of dynamic instability, manifested in their intermittent growth and shrinkage at both ends. This behavior is key to many cellular processes, such as cell division, migration, maintenance of cell shape, etc. Although assembly and disassembly of microtubules is known to be linked to hydrolysis of a guanosine triphosphate molecule in the pocket of β-tubulin, detailed mechanistic understanding of corresponding conformational changes is still lacking. Here we take advantage of the recent generation of in-microtubule structures of tubulin to examine the properties of protofilaments, which serve as important microtubule assembly and disassembly intermediates. We find that initially straight tubulin protofilaments, relax to similar non-radially curved and slightly twisted conformations. Our analysis further suggests that guanosine triphosphate hydrolysis primarily affects the flexibility and conformation of the inter-dimer interface, without a strong impact on the shape or flexibility of αβ-heterodimer. Inter-dimer interfaces are significantly more flexible compared to intra-dimer interfaces. We argue that such a difference in flexibility could be key for distinct stability of the plus and minus microtubule ends. The higher flexibility of the inter-dimer interface may have implications for development of pulling force by curving tubulin protofilaments during microtubule disassembly, a process of major importance for chromosome motions in mitosis.

30 citations

Journal ArticleDOI
TL;DR: In this article, the formation of straight oligomers of critical size is essential for nucleation of microtubules (MTs), but its mechanism is unknown because of the difficulty involved in capturing rare stochastic events in the early stage of polymerization.
Abstract: Nucleation of microtubules (MTs) is essential for cellular activities, but its mechanism is unknown because of the difficulty involved in capturing rare stochastic events in the early stage of polymerization Here, combining rapid flush negative stain electron microscopy (EM) and kinetic analysis, we demonstrate that the formation of straight oligomers of critical size is essential for nucleation Both GDP and GTP tubulin form single-stranded oligomers with a broad range of curvatures, but upon nucleation, the curvature distribution of GTP oligomers is shifted to produce a minor population of straight oligomers With tubulin having the Y222F mutation in the β subunit, the proportion of straight oligomers increases and nucleation accelerates Our results support a model in which GTP binding generates a minor population of straight oligomers compatible with lateral association and further growth to MTs This study suggests that cellular factors involved in nucleation promote it via stabilization of straight oligomers

27 citations

Journal ArticleDOI
TL;DR: It is proposed that the displacement of these secondary structures towards α‐tubulin may be used as a predictor of the effect of taxanes on the tubulin heterodimers in rational drug design approaches.
Abstract: The clinically approved taxanes (paclitaxel, docetaxel and cabazitaxel) target the tubulin protein in microtubules Despite the clinical success of these agents, the mechanism of action of this class of drugs remains elusive, making rational design of taxanes difficult Molecular dynamics simulations of these three taxanes with the αβ-tubulin heterodimer examine the similarities and differences in the effects of the drugs on tubulin, probing both local and allosteric effects Despite their structural similarity, the drugs adopt different conformations in the binding site on β-tubulin The taxanes similarly increase the helical character of α- and β-tubulins No correlations are found between microtubule assembly and (i) binding affinity or (ii) the role of the M-loop in enhancing lateral contacts Instead, changes in intra- and interdimer longitudinal contacts are indicative of the mechanism of action of the taxanes We find β:H1-S1', and more importantly β:H9 and β:H10, play a role translating the effect of local drug binding in β-tubulin to an allosteric effect in α-tubulin and propose that the displacement of these secondary structures towards α-tubulin may be used as a predictor of the effect of taxanes on the tubulin heterodimers in rational drug design approaches

23 citations

Journal ArticleDOI
TL;DR: The results suggest that even in assembled microtubules, both GTP‐ and GDP‐tubulin dimers can undergo dynamic conversion between at least two different states: short and long configurations.
Abstract: Microtubules are key components of the cytoskeleton in eukaryotic cells. The dynamics between assembled microtubules and free tubulin dimers in the cytoplasm is closely related to the active shape changes of microtubule networks. One of the most fundamental questions is the association of microtubule dynamics with the molecular conformation of tubulin within microtubules. To address this issue, we applied a new technique for the rapid shear-flow alignment of biological filaments, enabling us to acquire the structural periodicity data of microtubules by X-ray fiber diffraction under various physiological conditions. We classified microtubules into three main groups on the basis of distinct axial tubulin periodicities and mean microtubule diameters that varied depending on GTP hydrolysis and the content of paclitaxel, a microtubule stabilizer. Paclitaxel induced rapid changes in tubulin axial repeats in a cooperative manner. This is the first demonstration of dynamic changes of axial tubulin repeats within native microtubules without fixation. We also found extraordinary features of negative thermal expansion of axial tubulin repeats in both paclitaxel-stabilized and GMPCPP-containing microtubules. Our results suggest that even in assembled microtubules, both GTP- and GDP-tubulin dimers can undergo dynamic conversion between at least two different states: short and long configurations.

17 citations

Journal ArticleDOI
TL;DR: Results suggest that the nucleotide binding subdomain of FtsZ can switch between multitudes of curved conformations in all nucleotide states, but it prefers to be in an assembly competent less curved conformation in the GTP-bound state.
Abstract: The mechanism of nucleotide-regulated assembly and disassembly of the prokaryotic cell division protein FtsZ is not yet clearly understood. In this work, we attempt to characterize the functional motions in monomeric FtsZ through molecular dynamics simulations and essential dynamics (ED) analyses and correlate those motions to FtsZ assembly and disassembly. Results suggest that the nucleotide binding subdomain of FtsZ can switch between multitudes of curved conformations in all nucleotide states, but it prefers to be in an assembly competent less curved conformation in the GTP-bound state. Further, the GDP to GTP exchange invokes a subtle conformational change in the nucleotide binding pocket that tends to align the top portion of core helix H7 along the longitudinal axis of the protein. ED analyses suggest that the longitudinal movements of H7 and the adjacent H6–H7 region modulate the motions of C-domain elements coherently. These longitudinal movements of functionally relevant H7, H6–H7, T3, T7, and H1...

17 citations