Structural and Dynamic Insights into Podocalyxin-Ezrin Interaction as a Target in Cancer Progression.

Area of Science:

• Molecular biology and cancer research.
• Structural biology and computational biophysics.

Background:

• Cancer metastasis drives over 90% of cancer deaths, necessitating understanding of its molecular drivers.
• Podocalyxin (PODXL) is overexpressed in aggressive cancers, interacting with the actin-binding protein Ezrin to influence cell behavior.
• The structural and functional basis of the PODXL-Ezrin interaction, crucial for cancer progression, remains poorly understood and therapeutically challenging.

Purpose of the Study:

• To elucidate the structural mechanisms underlying the PODXL-Ezrin interaction.
• To investigate the impact of the PODXL R495W mutation on Ezrin binding and activation.
• To identify potential therapeutic strategies targeting the PODXL-Ezrin complex in cancer.

Main Methods:

• Integrated computational approach including protein-protein docking and molecular dynamics (MD) simulations.
• Utilized AlphaFold-predicted structures for modeling PODXL-Ezrin complexes.
• Performed virtual screening to identify small molecules interacting with the PODXL-Ezrin complex.

Main Results:

• PODXL's cytoplasmic domain stabilizes upon Ezrin binding, with Arg495 playing a key role in initial complex assembly.
• The PODXL R495W mutation allosterically destabilizes Ezrin's dormant conformation, potentially priming it for activation and enhancing oncogenic signaling.
• NSC305787 was identified as a selective destabilizer of the R495W mutant complex, disrupting critical interactions and hindering PIP2 recruitment.

Conclusions:

• The study reveals mutation-dependent structural changes in the PODXL-Ezrin complex, offering insights into cancer progression mechanisms.
• Findings highlight the potential of targeting specific PODXL-Ezrin interactions for cancer therapy.
• Identified NSC305787 as a promising lead compound for developing treatments for PODXL-altered cancers.