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Relating molecular flexibility to function: a case study of tubulin
Ozlem Keskin1, Stewart R Durell, Ivet Bahar
1Computational Technologies Laboratory, Screening Technologies Branch, Developmental Therapeutics Program, National Cancer Institute-Frederick, National Institutes of Health, Frederick, Maryland 21702 USA. okeskin@ku.edu.tr
Biophysical Journal
|July 19, 2002
Summary
This study reveals how tubulin dimer dynamics influence microtubule assembly and function. Understanding these movements, particularly those affected by drugs like paclitaxel, is key to microtubule-targeted therapies.
Area of Science:
- Molecular and Cellular Biology
- Biophysics
- Structural Biology
Background:
- Microtubules (MTs), composed of alpha/beta-tubulin heterodimers, are crucial for cellular processes like vesicle transport and cell division.
- Previous studies determined tubulin structure using electron crystallography of paclitaxel-stabilized sheets, providing a foundation for functional analysis.
- Understanding tubulin dimer dynamics is essential for elucidating its roles in polymerization, depolymerization, and interactions with motor proteins.
Purpose of the Study:
- To investigate the fluctuation dynamics of the tubulin dimer.
- To identify functional motions related to substrate binding, polymerization/depolymerization, and MT assembly.
- To explore the impact of the antitumor drug paclitaxel on tubulin dynamics.
Main Methods:
- Utilized a coarse-grained model, harmonically constrained to the crystal structure, to simulate global dynamics of the tubulin dimer.
- Analyzed collective motions and identified regions of dynamic behavior within the dimer.
- Investigated the effects of paclitaxel on tubulin flexibility.
Main Results:
- Identified six distinct regions of collective motion within the tubulin dimer, crucial for domain identification and function.
- Discovered that boundaries between these regions act as linkages, often located at hydrophobic residues and minima in fluctuation curves.
- Revealed that paclitaxel reduces flexibility in the beta-tubulin M loop, potentially enhancing lateral interactions in assembled microtubules.
Conclusions:
- Tubulin dimer dynamics, characterized by torsional, wobbling, and stretching motions, are intrinsically linked to microtubule organization and function.
- Specific dynamic regions, particularly loops and nucleotide-binding sites, are critical for tubulin function and are susceptible to mutations.
- Paclitaxel's effect on tubulin flexibility provides mechanistic insight into its antitumor activity by stabilizing microtubule structure.