Active and Inactive Cdc42 Differ in Their Insert Region Conformational Dynamics.

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Biology

Background:

• Cell division control protein 42 homolog (Cdc42) is a Ras superfamily GTPase crucial for cellular functions and cancer progression.
• Understanding the structural dynamics of Cdc42 in its active and inactive states is vital for deciphering its regulatory mechanisms.

Purpose of the Study:

• To investigate the structure and dynamics of GDP-bound (inactive) and GTP-bound (active) Cdc42 catalytic domains using molecular dynamics simulations.
• To identify conformational differences between active and inactive Cdc42 and their implications for effector binding and activation.

Main Methods:

• All-atom molecular dynamics (MD) simulations.
• Essential dynamic analysis.
• Simulation of oncogenic mutations (G12V, Q61L) in Cdc42.

Main Results:

• Significant dynamic differences were observed between GDP-bound and GTP-bound Cdc42, particularly in the insert region (residues 122-135).
• The insert region exhibits greater flexibility in the GDP-bound state, while switch regions show conformational changes in both states.
• Mutations G12V and Q61L affect Cdc42's GTPase activity and conformational dynamics, similar to K-Ras mutations.

Conclusions:

• Conformational dynamics, especially in the insert and switch regions, are key to Cdc42 nucleotide binding and activation.
• Disruption of hydrogen bonds in GDP-bound Cdc42 contributes to its distinct dynamics compared to other Rho GTPases.
• The inactive Cdc42 conformation may have a reduced capacity for effector binding, influencing cellular processes and cancer.