Abstract
SummaryCell migration requires coordination between integrin-mediated cell adhesion to the extracellular matrix and force applied to adhesion sites. Talin plays a key role in coupling integrin receptors to the actomyosin contractile machinery, while deleted in liver cancer 1 (DLC1) is a Rho GAP that binds talin and regulates Rho, and therefore actomyosin contractility. We show that the LD motif of DLC1 forms a helix that binds to the four-helix bundle of the talin R8 domain in a canonical triple-helix arrangement. We demonstrate that the same R8 surface interacts with the paxillin LD1 and LD2 motifs. We identify key charged residues that stabilize the R8 interactions with LD motifs and demonstrate their importance in vitro and in cells. Our results suggest a network of competitive interactions in adhesion complexes that involve LD motifs, and identify mutations that can be used to analyze the biological roles of specific protein-protein interactions in cell migration.
Highlights
Integrin-mediated cell adhesion to the extracellular matrix (ECM) involves the assembly of dynamic adhesion complexes and requires the spatial and temporal coordination of signaling and force-transmitting events (Gardel et al, 2010; Wehrle-Haller, 2012)
We propose that LD-motif recognition sites in adhesion proteins such as talin and FAK are to a large degree interchangeable, creating a network of competing protein-protein interactions that regulate the properties of adhesion complexes
Based on the talin/deleted in liver cancer 1 (DLC1) structure, we predicted that talin R8 might bind paxillin LD motifs; we demonstrate such an interaction by nuclear magnetic resonance (NMR) and glutathione S-transferase (GST) pull-downs, Structure of the DLC1/Talin Complex The talin binding site (TBS) in DLC1 has been shown to require an 8-residue peptide 469LDDILYHV476 located in the largely unstructured linker region between the SAM and GAP domains of DLC1 (Figure 1B) (Li et al, 2011)
Summary
Integrin-mediated cell adhesion to the extracellular matrix (ECM) involves the assembly of dynamic adhesion complexes and requires the spatial and temporal coordination of signaling and force-transmitting events (Gardel et al, 2010; Wehrle-Haller, 2012). Such complexes form on the cytoplasmic tails of integrin receptors and mature into larger structures called focal adhesions (FA) in response to force exerted by the actomyosin contractile apparatus (Roca-Cusachs et al, 2012). Disruption of the talin force-sensing mechanism has strong effects on adhesion assembly, cell polarization, and cell migration (Atherton et al, 2015)
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