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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
PubMed

Insights

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.

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