9QWO

Vinculin tail bound to paxillin LD2

Summary for 9QWO

• Entry DOI: 10.2210/pdb9qwo/pdb
• Descriptor: Isoform 1 of Vinculin, Isoform Gamma of Paxillin, Paxillin, ... (6 entities in total)
• Functional Keywords: focal adhesions, force transduction, vinculin, paxillin, cell adhesion
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 8
• Total formula weight: 89246.57

Authors

Diaz-Palacios, K.,Lietha, D. (deposition date: 2025-04-14, release date: 2025-04-23, Last modification date: 2025-05-07)

Primary citation

Diaz-Palacios, K.,Lopez Navajas, P.,Rodrigo Martin, B.,Matesanz, R.,Luque-Ortega, J.R.,Echarri, A.,Lietha, D.
Phospho-regulated tethering of focal adhesion kinase to vinculin links force transduction to focal adhesion signaling.
Cell Commun Signal, 23:190-190, 2025

PubMed Abstract: Focal Adhesion Kinase (FAK) is a key signaling molecule in focal adhesions (FAs) orchestrating the formation, maturation and turnover of the FA complex. A controlled FA lifecycle is essential for various cellular processes requiring mesenchymal cell migration and is harnessed by advanced cancers to initiate cancer invasion and metastasis. The mechanical force for migration is transmitted from actin stress fibers to FAs via specialized force transduction components in FAs. These forces are known to activate FA signaling, suggesting a communication between FA force transduction and FA signaling components, yet how this occurs mechanistically is unknown. Here we demonstrate that paxillin can act as an adaptor protein to connect FAK with the force transduction component vinculin. Our data show that this connection forms inefficient in the basal state but suggest Y925 phosphorylation in FAK as a key mechanism for optimal formation of the FAK:paxillin:vinculin linkage. This is achieved by switching binding of the paxillin LD2 motif from FAK to vinculin while keeping paxillin LD4 tethered to FAK. We further provide the first high-resolution crystal structure of LD2 bound to the vinculin tail domain, which importantly shows that vinculin can simultaneously link to actin. This therefore ensures an intact force transduction role of vinculin while tethered via paxillin to the signaling apparatus in FAs. With this data, all interactions of the force transmitting tether to FAK are structurally defined and we provide an atomic model for FAK force activation. In summary, we propose a phospho-regulated connection between signaling and force transduction components in FAs allowing for force induced activation of FA signaling.

PubMed: 40259376
DOI: 10.1186/s12964-025-02201-3

Experimental method

X-RAY DIFFRACTION (2.54 Å)