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Functional specificity conferred by the unique plasticity of fully alpha-helical Ras and Rho GAPs
M Souchet1, A Poupon, I Callebaut
1SmithKline Beecham Laboratoires Pharmaceutiques, 4 rue Chesnay- Beauregard, 35760 Saint-Grégiure, France.
FEBS Letters
|July 19, 2000
Summary
Structural analysis reveals that p120 and p50 GTPase-activating proteins (GAPs) share a common evolutionary origin and flexible core structure. This plasticity allows GAPs to specifically recognize and regulate small GTPases.
Area of Science:
- Biochemistry
- Structural Biology
- Molecular Biology
Background:
- GTPase-activating proteins (GAPs) regulate small GTPases, crucial for cellular signaling.
- p120 and p50 are distinct GAPs that interact with Ras and Rho GTPases, respectively.
Purpose of the Study:
- To decipher the functional roles of specific structural features in p120 and p50 GAPs.
- To identify key residues involved in GAP/GTPase complex stabilization.
- To investigate the evolutionary relationship and common structural elements between different GAP families.
Main Methods:
- Comparative structural analysis of p120-Ras and p50-Rho complexes.
- Identification of conserved topohydrophobic positions across GAP families.
- Analysis of helix rearrangements and conserved structural cores.
Main Results:
- Specific helices (alpha8c in p120, A1 in p50) are critical for small GTPase recognition.
- Key residues stabilizing GAP/GTPase binary complexes were identified.
- A conserved flexible four-helix bundle common to both GAP families was characterized.
- Evidence suggests p50 and p120 GAPs evolved from a unique ancestral fold.
Conclusions:
- GAPs exhibit remarkable structural plasticity, enabling functional specificity.
- The identified common core and helix rearrangements support a shared evolutionary origin for p120 and p50 GAPs.
- Structural flexibility is a key mechanism for precise regulation of small GTPase activity.