A Triple-pose Complex Between an Extended WIP

During cancer development, cancer cells degrade the extracellular matrix to enable tumor invasion into surrounding tissues. This process is enhanced by cortactin, a key regulator of metalloproteinase secretion and a biomarker for metastatic cancer. In a study published in the Journal of Molecular Biology, Dr. Chana Sokolik and Prof. Jordan Chill used NMR-based structural analysis methods to characterize the interaction between cortactin and WASp-interacting protein (WIP), an association required for the invasive phenotype of cancer cells. The researchers identified the SH3 domain of cortactin (cortSH3) and an extended, proline-rich hydrophobic segment of WIP as the interaction sites. Analysis of edited-filtered NOESY (Nuclear Overhauser Effect SpectroscopY) experiments revealed three interchanging binding modes: two canonical orientations and a third, non-canonical pose engaging a previously underappreciated surface. Mutational analysis confirmed that these poses depend on both electrostatic and hydrophobic interactions. These structural insights suggest potential therapeutic strategies for metastatic cancer by targeting WIP and disrupting the cortSH3-WIP interaction.