Structure of an integrin αIIbβ3 transmembrane-cytoplasmic heterocomplex provides insight into integrin activation

Yang, Jun; Qing, Ying; Page, Richard C.; Misra, Saurav; Plow, Edward F.; Qin, Jun

doi:10.1073/pnas.0909589106

Cited by 146 publications

(187 citation statements)

References 41 publications

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“…S1) that have been shown to interact with the Nterminal a IIb CT MP region in a NMR structure of membraneanchored a IIb CT peptide (Vinogradova et al, 2000). This interaction might be important in keeping the resting integrin state, but the same interaction was not found in the NMR structure of the a IIb b 3 TM-CT heterodimer determined in organic solvent (Yang et al, 2009) (Fig. 1C).…”

Section: Icam-1 Binding (Nomalized Mfi)mentioning

confidence: 76%

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The dual structural roles of the membrane distal region of α integrin cytoplasmic tail in integrin inside-out activation

Liu¹,

Wang²,

Thinn³

et al. 2015

Journal of Cell Science

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BSTRACTStudies on the mechanism of integrin inside-out activation have been focused on the role of b-integrin cytoplasmic tails, which are relatively conserved and bear binding sites for the intracellular activators including talin and kindlin. Cytoplasmic tails for a-integrins share a conserved GFFKR motif at the membrane-proximal region and this forms a specific interface with the b-integrin membraneproximal region to keep the integrin inactive. The a-integrin membrane-distal regions, after the GFFKR motif, are diverse both in length and sequence and their roles in integrin activation have not been well-defined. In this study, we report that the a-integrin cytoplasmic membrane-distal region contributes to maintaining integrin in the resting state and to integrin inside-out activation.Complete deletion of the a-integrin membrane-distal region diminished talin-and kindlin-mediated integrin ligand binding and conformational change. A proper length and suitable amino acids in a-integrin membrane-distal region was found to be important for integrin inside-out activation. Our data establish an essential role for the a-integrin cytoplasmic membrane-distal region in integrin activation and provide new insights into how talin and kindlin induce the high-affinity integrin conformation that is required for fully functional integrins.

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Section: Icam-1 Binding (Nomalized Mfi)mentioning

confidence: 76%

“…1A) and by NMR using the isolated peptides either in lipid bicelles (Fig. 1B) or in organic solvent (Yang et al, 2009) (Fig. 1C).…”

Section: Introductionmentioning

confidence: 99%

The dual structural roles of the membrane distal region of α integrin cytoplasmic tail in integrin inside-out activation

Liu¹,

Wang²,

Thinn³

et al. 2015

Journal of Cell Science

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“…Previous studies reported on the interaction of the talin-1 FERM domain and the β3 CT with micelles and phospholipid vesicles (15,27,(38)(39)(40). Here, we studied these interactions using a β3 CT construct tethered to phospholipid bilayers to understand the energetics of the overall process.…”

Section: Discussionmentioning

confidence: 99%

Affinity of talin-1 for the β3-integrin cytosolic domain is modulated by its phospholipid bilayer environment

Moore

Nygren

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Binding of the talin-1 FERM (4.1/ezrin/radixin/moesin) domain to the β3 cytosolic tail causes activation of the integrin αIIbβ3. The FERM domain also binds to acidic phospholipids. Although much is known about the interaction of talin-1 with integrins and lipids, the relative contribution of each interaction to integrin regulation and possible synergy between them remain to be clarified. Here, we examined the thermodynamic interplay between FERM domain binding to phospholipid bilayers and to its binding sites in the β3 tail. We found that although both the F0F1 and F2F3 subdomains of the talin-1 FERM domain bind acidic bilayers, the full-length FERM domain binds with an affinity similar to F2F3, indicating that F0F1 contributes little to the overall interaction. When free in solution, the β3 tail has weak affinity for the FERM domain. However, appending the tail to acidic phospholipids increased its affinity for the FERM domain by three orders of magnitude. Nonetheless, the affinity of the FERM for the appended tail was similar to its affinity for binding to bilayers alone. Thus, talin-1 binding to the β3 tail is a ternary interaction dominated by a favorable surface interaction with phospholipid bilayers and set by lipid composition. Nonetheless, interactions between the FERM domain, the β3 tail, and lipid bilayers are not optimized for a high-affinity synergistic interaction, even at the membrane surface. Instead, the interactions appear to be tuned in such a way that the equilibrium between inactive and active integrin conformations can be readily regulated.cytoskeleton | plasma membrane | platelet aggregation T he integrin αIIbβ3 resides on the platelet surface in equilibrium between resting and active conformations (1-5). On circulating platelets, αIIbβ3 is constrained in its inactive conformation to prevent spontaneous platelet aggregation. Similarly, the cytoskeletal protein talin-1, whose binding to the β3 cytosolic tail (CT) stabilizes the active conformation of αIIbβ3 (6-8), is sequestered away from the β3 CT (9). Besides interacting with integrins, talin-1 interacts with negatively charged phospholipids (10-12) and phosphoinositides (13)(14)(15)(16). Stimuli generated at sites of vascular damage recruit talin-1 to the platelet plasma membrane, thereby promoting αIIbβ3 activation (17-19). Much is known about the interaction of talin-1 with integrins and lipids, but the relative contribution of each interaction to integrin regulation and possible synergy between them remain to be clarified. Elucidating these interactions is important for understanding events leading to and controlling the formation of integrin complexes and for potential pharmacologic modulation of integrin signaling.Talin-1 is a 250-kD protein containing a 45-kD N-terminal head domain attached via a flexible linker to a 200-kD C-terminal rod domain (7). Because the head domain is packed against the rod domain in its inactive state (20), talin-1 recruitment to the membrane and to integrin β CTs requires disruption of this interaction (1...

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“…inside-out signaling (Dai et al, 2015;Ginsberg et al, 2005). The activation states of integrins are tightly controlled by interactions between α-and β-subunits at both the membrane-proximal cytoplasmic tails (CTs) and the transmembrane domains (Vinogradova et al, 2002;Yang et al, 2009;Zhu et al, 2009). Integrin conformational changes toward active states can be triggered by the binding of cytoplasmic integrin activators to the integrin β CTs (Liu et al, 2000;Ma et al, 2007;Moser et al, 2009b;Qin et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Kindlin supports platelet integrin αIIbβ3 activation by interacting with paxillin

Gao

Huang

Lai

et al. 2017

Journal of Cell Science

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Kindlins play an important role in supporting integrin activation by cooperating with talin; however, the mechanistic details remain unclear. Here, we show that kindlins interacted directly with paxillin and that this interaction could support integrin αIIbβ3 activation. An exposed loop in the N-terminal F 0 subdomain of kindlins was involved in mediating the interaction. Disruption of kindlin binding to paxillin by structure-based mutations significantly impaired the function of kindlins in supporting integrin αIIbβ3 activation. Both kindlin and talin were required for paxillin to enhance integrin activation. Interestingly, a direct interaction between paxillin and the talin head domain was also detectable. Mechanistically, paxillin, together with kindlin, was able to promote the binding of the talin head domain to integrin, suggesting that paxillin complexes with kindlin and talin to strengthen integrin activation. Specifically, we observed that crosstalk between kindlin-3 and the paxillin family in mouse platelets was involved in supporting integrin αIIbβ3 activation and in vivo platelet thrombus formation. Taken together, our findings uncover a novel mechanism by which kindlin supports integrin αIIbβ3 activation, which might be beneficial for developing safer anti-thrombotic therapies.

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Structure of an integrin αIIbβ3 transmembrane-cytoplasmic heterocomplex provides insight into integrin activation

Cited by 146 publications

References 41 publications

The dual structural roles of the membrane distal region of α integrin cytoplasmic tail in integrin inside-out activation

The dual structural roles of the membrane distal region of α integrin cytoplasmic tail in integrin inside-out activation

Affinity of talin-1 for the β3-integrin cytosolic domain is modulated by its phospholipid bilayer environment

Kindlin supports platelet integrin αIIbβ3 activation by interacting with paxillin

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