Researchers Uncover How Key Cell Proteins Interact with Implications for Cancer Treatment

How do cells coordinate activities between their insides and their outside? A new study published in Science Advances by researchers from the University of Maryland (UMD), the National Institute of Standards and Technology (NIST), and the City of Hope Medical Center provides a molecular-level answer. The research uncovers novel insights into the Focal Adhesion (FA) complex, specifically how two key proteins - paxillin and the Focal Adhesion Targeting (FAT) domain - interact to form a critical structural connection between the cell’s internal cytoskeleton and the external extracellular matrix. This link enables cells to "sense" and respond to their environment, coordinating processes such as signaling, adhesion, and migration.

The study, entitled “Conformational Dynamics and Multi-Modal Interaction of Paxillin with the Focal Adhesion Targeting Domain,” sheds light on how communication between the inside and outside of cells is physically and functionally achieved. Despite the known importance of paxillin (PXN) and the Focal Adhesion Kinase (FAK), it had remained unclear how PXN’s disordered nature changes upon binding to the FAT domain of FAK. The large size and dynamic behavior of these components had posed significant challenges to structural characterization.

By integrating a combination of advanced techniques including NMR, small-angle X-ray scattering, and molecular dynamics simulations, the researchers achieved an extensive characterization of the interaction. They discovered that PXN undergoes significant compaction upon binding to FAT and can shift between four different conformations. In its unbound state, PXN remains flexible, enabling interactions with other focal adhesion molecules. This dynamic behavior is believed to be central to the function of the FA complex and may have broader relevance for studying other intrinsically disordered proteins.

In addition to the biological insights, the study demonstrates the power of combining multiple structural techniques to analyze flexible and challenging protein systems. John Orban, IBBR Fellow and Professor in the Department of Chemistry & Biochemistry at UMD, and a senior author of the study, noted that “this work may also lead to potential new therapeutic targets, as the interacting proteins are involved in cancer metastasis and drug resistance.”