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Control of intrinsically disordered stathmin by multisite phosphorylation.
Srinivas Honnappa1, Wolfgang Jahnke, Joachim Seelig
1Biomolecular Research, Structural Biology, Paul Scherrer Insititut, CH-5232 Villigen PSI, Switzerland.
The Journal of Biological Chemistry
|March 24, 2006
Summary
Stathmin phosphorylation reduces its ability to destabilize microtubules by altering tubulin binding. This provides a biophysical explanation for how stathmin activity gradients regulate microtubule growth.
Area of Science:
- Biophysics
- Molecular Biology
- Cancer Research
Background:
- Stathmin is an intrinsically disordered protein crucial for microtubule dynamics.
- Its activity, which promotes microtubule destabilization, is regulated by phosphorylation.
- Dysregulation of stathmin is linked to cancer development.
Purpose of the Study:
- To investigate the biophysical properties of stathmin phosphoisoforms.
- To analyze the impact of phosphorylation on tubulin binding and microtubule inhibition.
- To elucidate the molecular mechanisms underlying stathmin's regulatory role.
Main Methods:
- Calorimetric and spectroscopic techniques were employed.
- Nuclear magnetic resonance (NMR) was used to study seven stathmin phosphoisoforms.
- Tubulin binding and microtubule formation inhibition were analyzed.
Main Results:
- Stathmin phosphorylation significantly decreases hydration entropy upon tubulin complex formation.
- A direct correlation exists between the free energy of complex formation and microtubule inhibition activity.
- Phosphorylation at Ser16 and Ser63 disrupts key structural elements (beta-hairpin and helix) involved in tubulin interaction.
Conclusions:
- Phosphorylation modulates stathmin's interaction with tubulin through changes in hydration entropy.
- This provides a biophysical basis for stathmin's role in regulating microtubule dynamics and cell cycle progression.
- The findings offer insights into the behavior of intrinsically disordered proteins.