Key Points
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Integrins are transmembrane receptors that support adhesion to the extracellular matrix and transmit chemical and mechanical signals into and out of cells. Cells regulate integrin-mediated adhesion by controlling integrin affinity for extracellular ligands (integrin activation), by clustering integrins into adhesion complexes (avidity modulation) and by regulating links between integrin cytoplasmic domains and the actin cytoskeleton.
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The large dimeric actin-binding protein talin is a key regulator of integrin activation, and is composed of an amino-terminal head and a carboxy-terminal flexible rod. The structures of all 18 domains in talin have now been determined, and a model of full-length talin has been generated.
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Biochemical and structural data reveal how direct interactions between the short cytoplasmic tails of β-integrin subunits and the talin head (a FERM domain) disrupt inhibitory interactions between the integrin α-subunit and β-subunit, inducing conformational changes in the integrin extracellular domains that result in their increased affinity for ligand.
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The talin rod consists of 13 either 4- or 5-helix bundles, terminating in a single helix that supports talin dimerization. It contains two actin-binding sites and multiple binding sites for the actin-binding protein vinculin, which stabilizes adhesion complexes. Recent data show that the dynamic between talin–RIAM and talin–vinculin interactions is important for integrin activation and force-induced maturation of adhesions.
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Regulation of talin–integrin interactions represents an important control point along integrin activation pathways. Various regulatory mechanisms have been identified, including talin autoinhibition, competition between talin and other integrin tail-binding or talin-binding proteins and post-translational modification of β-integrin subunits.
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Although much less well-understood than talins, kindlin family proteins are also known to be important integrin regulators. Kindlin loss, due to knockout, knockdown or disease-causing mutations, result in defective integrin activation.
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The molecular basis of kindlin function has yet to be determined, but kindlins are structurally related to the talin head, directly bind β-integrin tails and membranes, localize to focal adhesions and synergize with talin during integrin activation.
Abstract
Integrin receptors provide a dynamic, tightly-regulated link between the extracellular matrix (or cellular counter-receptors) and intracellular cytoskeletal and signalling networks, enabling cells to sense and respond to their chemical and physical environment. Talins and kindlins, two families of FERM–domain proteins, bind the cytoplasmic tail of integrins, recruit cytoskeletal and signalling proteins involved in mechanotransduction and synergize to activate integrin binding to extracellular ligands. New data reveal the domain structure of full-length talin, provide insights into talin-mediated integrin activation and show that RIAM recruits talin to the plasma membrane, whereas vinculin stabilizes talin in cell–matrix junctions. How kindlins act is less well-defined, but disease-causing mutations show that kindlins are also essential for integrin activation, adhesion, cell spreading and signalling.
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Acknowledgements
Work in the authors laboratories was supported by the National Institutes of Health (NIH), the Medical Research Council, the Wellcome Trust, Cancer Research UK and the Medical Research Council. They thank members of the Calderwood laboratory for their input during preparation of the mansucript, B. Goult for help in preparing figure 1 and A. Kalli for contributions to figure 2c. They apologize to colleagues whose work could not be cited or fully discussed due to space limitations.
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FURTHER INFORMATION
Glossary
- FERM domain
-
Found in various cytoskeletal-associated proteins, including band 4.1, ezrin, radixin and moesin, the proteins after which this domain was named. One role of this domain is to localize proteins to the plasma membrane. It typically contains three subdomains, F1, F2 and F3, that normally arranged in a cloverleaf formation.
- Nanodiscs
-
A synthetic model membrane system made from lipids and a scaffold protein. They are used to study incorporated membrane proteins, such as integrins, because they are relatively small, monodisperse and homogenous, yet provide a native-like environment.
- Leukocyte adhesion deficiency type III
-
(LADIII). A rare genetic disease characterized by severe bacterial infections and bleeding disorders. It is caused by mutations in the gene encoding kindlin 3 in haematopoietic cells.
- Multiscale molecular dynamics simulations
-
These numerically solve Newton's equations for interacting particles and follow their trajectories. They have become a powerful way of fine-tuning protein structure and dynamics. Major limitations are the relatively small size of the systems and the short timescales of the trajectories that can be studied. Multiscale simulations that combine simplified representations of molecules (coarse grain) with all atom representations (atomistic) circumvent some limitations.
- SAXS
-
(Small angle X-ray scattering). A technique that provides low-resolution information about the shape of objects. It depends on the analysis of the angular intensity distribution of X-rays scattered by molecules in solution.
- RAS-associating domain
-
(RA domain). A domain that is found in many effector proteins for the RAS family of small GTPases. The domain adopts a ubiquitin-like fold and supports binding of proteins containing an RA domain to 'active' GTP-loaded RAS family proteins.
- Pleckstrin homology domain
-
(PH domain). Domain that is found in a wide range of intracellular signalling proteins. It often binds to membranes via interactions with phosphatidylinositol-4,5-bisphosphate.
- Exocyst complex
-
An octameric protein complex that is involved in vesicle trafficking. It targets post-Golgi vesicles to the plasma membrane before vesicle fusion.
- PTB domain
-
(Phosphotyrosine-binding domain). Domain found in a wide range of intracellular signalling proteins. It commonly binds NPXY motifs; the Y may require phosphorylation to support binding.
- KRIT1
-
(Krev interaction trapped 1). This protein, which is encoded by the CCM1 gene, is a multidomain adaptor that is important for cell–cell and cell–matrix adhesion. Loss-of-function mutations in CCM1 cause predisposition to cerebral cavernous malformations, which are neurovascular anomalies that increase the risk of haemorrhagic stroke.
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Calderwood, D., Campbell, I. & Critchley, D. Talins and kindlins: partners in integrin-mediated adhesion. Nat Rev Mol Cell Biol 14, 503–517 (2013). https://doi.org/10.1038/nrm3624
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DOI: https://doi.org/10.1038/nrm3624
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