Abstract
The cytoskeletal protein talin plays a key role in activating integrins and in coupling them to the actin cytoskeleton. Its N-terminal globular head, which binds beta integrins, is linked to an extended rod having a C-terminal actin binding site and several vinculin binding sites (VBSs). The NMR structure of residues 755-889 of the rod (containing a VBS) is shown to be an amphipathic four-helix bundle with a left-handed topology. A talin peptide corresponding to the VBS binds the vinculin head; the X-ray crystallographic structure of this complex shows that the residues which interact with vinculin are buried in the hydrophobic core of the talin fragment. NMR shows that the interaction involves a major structural change in the talin fragment, including unfolding of one of its helices, making the VBS accessible to vinculin. Interestingly, the talin 755-889 fragment binds more than one vinculin head molecule, suggesting that the talin rod may contain additional as yet unrecognized VBSs.
Highlights
The integrin family of transmembrane αβ heterodimers is important in both cell-cell and cell extracellular matrix interactions
We report the solution structure of an adjacent region of the talin rod that contains another vinculin binding site, VBS2, together with studies of its interaction with the vinculin head by crystallography and NMR
We show that the interaction of talin VBS2 with vinculin is similar to that reported for VBS3 (Izard et al, 2004) and, importantly, that this interaction requires a major structural change in talin 755–889, including complete unfolding of one of its four helices
Summary
The integrin family of transmembrane αβ heterodimers is important in both cell-cell and cell extracellular matrix interactions. Though not all, cases they are coupled to the actin cytoskeleton via proteins such as talin, α actinin, filamin, and tensin (Liu et al, 2000), a link which is important to actomyosin-driven cell migration and the signaling pathways that regulate cell proliferation and apoptosis. Talin has recently been shown to activate integrins (Tadokoro et al, 2003) by dissociating the interaction between the α/β-cytoplasmic domains (Kim et al, 2003). The biochemical and structural properties of talin are consistent with such a role.
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