Reconstruction of integrin activation - PubMed (original) (raw)

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Reconstruction of integrin activation

Feng Ye et al. Blood. 2012.

Abstract

Integrins are integral membrane proteins that mediate cell-matrix and cell-cell adhesion. They are important for vascular development and hematopoiesis, immune and inflammatory responses, and hemostasis. Integrins are also signaling receptors that can transmit information bidirectionally across plasma membranes. Research in the past 2 decades has made progress in unraveling the mechanisms of integrin signaling and brings the field to the moment of attempting synthetic reconstruction of the signaling pathways in vitro. Reconstruction of biologic processes provides stringent tests of our understanding of the process, as evidenced by studies of other biologic machines, such as ATP synthase, lactose permease, and G-protein-coupled receptors. Here, we review recent progress in reconstructing integrin signaling and the insights that we have gained through these experiments.

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Figures

Figure 1

Figure 1

Structural model of talin-integrin interaction at the plasma membrane. Talin binds to 2 sites in the integrin-β3 tail: the membrane distal (MD) interaction site centered on NPxY747 motif and a membrane proximal (MP) site. Talin also makes contact with the plasma membrane at its interface with the cytosol (yellow band) through the positively charged residues on its surface (represented as blue; red dotted lines represent the membrane contact interfaces). Red and green represent the integrin-αIIb and β3 TM domains from the recent NMR structure (PDB entry 2k9j). Talin head domain (PDB entry 3IVF) is shown in surface representation. The ribbon representation of β3 was extended to the cytoplasmic domain by aligning the β3 TM domain with the β1D cytoplasmic domain structure from a β1D-Talin F2F3 (PDB entry 3G9W).

Figure 2

Figure 2

Agonist-induced inside-out integrin signaling system reconstituted in CHO cells. (A) CHO cells normally do not respond to PMA. CHO cells overexpressing integrin-αIIbβ3, PKC-α, and talin responded to PMA, resulting in αIIbβ3 activation. (B) CHO cells do not respond to thrombin or related peptide agonists, CHO cells overexpressing αIIbβ3, PAR, and talin responded to thrombin receptor peptide agonist, leading to activation of Rap1, formation of a Rap1-RIAM-talin ternary complex, and αIIbβ3 activation.

Figure 3

Figure 3

Complete reconstruction of integrin inside-out activation with liposomes and nanodiscs. (A) Incorporation of THD into integrin liposomes resulted in activation of the externally oriented αIIbβ3. (B) Integrin-αIIbβ3 in nanodiscs is in an inactive bent conformation. Addition of THD resulted in the activation of αIIbβ3 leading to increased binding affinity for its ligand and a shift toward the extended conformation.

Figure 4

Figure 4

Integrin activation by various means. Red represents α-subunit; and blue, β-subunit. Activating agents are shown in green. (A) αLβ2-Integrin activation recreated by antibodies. CBR LFA-1/2 locks β2-integrin in extended conformation. MEM148 stabilizes the head piece in an open active conformation, whereas 7E4 locks it in a closed inactive conformation. Using a different combination of antibodies, Chen et al stabilized integrins in inactive, intermediate, or active state. For a complete description of antibodies, the reader is referred to Byron et al. (B) Integrin activation induced by synthetic peptides that bind to integrin TMD, by mutations, or by a glycan wedge.

References

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