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Lucky kindlin: A cloverleaf at the integrin tail

2017; National Academy of Sciences; Volume: 114; Issue: 35 Linguagem: Inglês

10.1073/pnas.1712471114

1091-6490

Patricia Kammerer, Jonas Aretz, Reinhard Fässler,

Signaling Pathways in Disease

In a paper published in PNAS, Li et al. (1) solve the long-awaited crystal structure of kindlin-2, which plays a central role in integrin activation, clustering, and signaling (2, 3). Integrins are a large family of heterodimeric adhesion molecules composed of α- and β-subunits and expressed on almost all cells. They mediate cell matrix adhesion by binding extracellular matrix proteins, such as collagens, fibronectin, and laminins, and cell–cell adhesion by interacting with counterreceptors such as VCAM, ICAM, and cadherins (Fig. 1 A ). Upon ligand binding, integrins cluster and assemble an enormous number of proteins at their short cytoplasmic domains, which are collectively called the adhesome (4). The adhesome transmits biochemical signals into the cell and connects integrins to the actin cytoskeleton, which, in turn, enables the transduction of myosin-II–generated traction forces to ligated integrins. Fig. 1. Kindlin and talin promote integrin activation. ( A ) Integrins are heterodimers (α, turquoise; β, red) that can adopt three conformations: BC, EC, or EO. The EO conformation, corresponding to the active conformation, is induced and/or stabilized by talin (violet) and kindlin (cyan), which bind to specific motifs in the β-integrin tail (magnified) and to charged lipids in the plasma membrane (yellow). The distribution of BC, EC, and EO conformations in equilibrium on K652 cells is depicted for α5β1 integrins. A model of a kindlin-2 monomer [F0–F3 modules (Protein Data Bank [PDB] ID code 5XPY, cyan)] and PH domain (PDB ID code 4F7H, green) ( B ) and a model of dimeric kindlin-2 (PDB ID code 5XQ0, cyan) ( C ) interacting with talin (PDB ID code 3G9W, violet) and the β1-integrin tail (red) are shown. Regions known to interact with charged lipids are highlighted in yellow. The PH domain was modeled into the structure to demonstrate its size and potential localization, whereas the flexible loop inserted into the F1 domain is … [↵][1]1To whom correspondence should be addressed. Email: faessler{at}biochem.mpg.de. [1]: #xref-corresp-1-1