The Structure of a Receptor with Two Associating Transmembrane Domains on the Cell Surface: Integrin αIIbβ3

Zhu, Jieqing; Luo, Bing Hao; Barth, Patrick; Schonbrun, Jack; Baker, David; Springer, Timothy A.

doi:10.1016/j.molcel.2009.02.022

Cited by 141 publications

(253 citation statements)

References 40 publications

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“…S5), indicating that both CD 3 CN/H 2 O mixture and bicelles provide environments compatible for TM complex assembly. Many different computational models of integrin TM complexes have been proposed (3-5, 11, 13, 15-18), but the 2 most recent ones (17,18) were found to be similar to the structure of Lau agreement for integrin TM assembly from the latest independent studies (including ours) using different methods.…”

Section: Correlation Of the Tmcd Interface With Integrin Mutation Datmentioning

confidence: 63%

“…S5), the different CT clasps (Fig. S5) involving either the ␣IIb KVGFF reverse turn or helix cannot be due to the lack of TM as stated by Zhu et al (17). Rather, different solvent systems (CD 3 CN/H 2 O vs. bicelles) in the 2 studies may have captured 2 different conformational states of an intrinsically flexible region.…”

Section: Correlation Of the Tmcd Interface With Integrin Mutation Datmentioning

confidence: 69%

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

Yang

Qing

Page

et al. 2009

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

146

179

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Heterodimeric integrin adhesion receptors regulate diverse biological processes including angiogenesis, thrombosis and wound healing. The transmembrane-cytoplasmic domains (TMCDs) of integrins play a critical role in controlling activation of these receptors via an inside-out signaling mechanism, but the precise structural basis remains elusive. Here, we present the solution structure of integrin ␣IIb␤3 TMCD heterodimer, which reveals a righthanded coiled-coil conformation with 2 helices intertwined throughout the transmembrane region. The helices extend into the cytoplasm and form a clasp that differs significantly from a recently published ␣IIb␤3 TMCD structure. We show that while a point mutation in the clasp interface modestly activates ␣IIb␤3, additional mutations in the transmembrane interface have a synergistic effect, leading to extensive integrin activation. Detailed analyses and structural comparison with previous studies suggest that extensive integrin activation is a highly concerted conformational transition process, which involves transmembrane coiled-coil unwinding that is triggered by the membrane-mediated alteration and disengagement of the membrane-proximal clasp. Our results provide atomic insight into a type I transmembrane receptor heterocomplex and the mechanism of integrin inside-out transmembrane signaling.NMR ͉ protein structure ͉ transmembrane domain I ntegrins are a major class of cell adhesion receptors that are found in almost every living organism (1). They are obligate heterodimers (␣,␤) in which each subunit is composed of a large extracellular domain, a single pass transmembrane (TM) segment, and a small cytoplasmic tail (CT). Integrins interact with extracellular matrix (ECM) proteins via their extracellular domains and with intracellular proteins via their CTs. This interconnection allows integrins to regulate diverse cellular adhesive processes. A central and unresolved issue in integrin biology is the molecular basis for signal transmission across the cell membrane. A large body of genetic, cell biological, and biochemical data indicate that the conformational states of integrin ␣/␤ transmembrane-cytoplasmic domains (TMCDs) control the ability of integrins to bind extracellular ligands (inside-out signaling) and to cluster and form focal adhesions (outside-in signaling) (for reviews see refs. 1 and 2). Biochemical and structural evidence suggests that the ␣/␤ TMCDs associate via both their TMs (3-6) and their CTs (7-9) to maintain integrins in a resting state. Dissociation of the TMs or CTs triggers receptor activation and signaling (7,(10)(11)(12)(13)(14). However, many different computational models for the TM association exist (3-5, 11, 13, 15-18) and the structural analyses of the CT interaction are inconsistent (6)(7)(8)(9)19). Earlier studies failed to observe heterodimeric TMCD interaction in micelles (20), which reflects the technical difficulty in structurally characterizing this kind of transmembrane heterodimers (21). Here, we have successfully determined the NMR ...

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Section: Correlation Of the Tmcd Interface With Integrin Mutation Datmentioning

confidence: 63%

Section: Correlation Of the Tmcd Interface With Integrin Mutation Datmentioning

confidence: 69%

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

Yang

Qing

Page

et al. 2009

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

146

179

View full text Add to dashboard Cite

show abstract

“…1B) (19). Mutations most disruptive of the DN effect of the β 3 helix occurred at residues L697, V700, I704, and G708, each of which has been identified as important for stabilizing the resting conformation of full-length α IIb β 3 (2-4, 6, 7), and in addition, are in proximity to α IIb based on disulfide-cross-linking and NMR measurements (11,12). The DN-ToxRed assay was then used to probe the association of the β 3 subunit with its other partner, α v , as well as the association of the β 1 TM domain with its partners α 2 and α 5 (Figs.…”

Section: Resultsmentioning

confidence: 99%

“…If this is the case, one might expect that the TM helices would form an autonomous interaction unit, engaging in a stable interaction even in the absence of extracellular and cytoplasmic domains. Indeed, early modeling studies suggested a specific geometric interaction (4, 9, 10), which has recently been supported by NMR and Cys cross-linking studies of the α IIb and β 3 TM helices (11,12).…”

mentioning

confidence: 87%

Consensus motif for integrin transmembrane helix association

Berger

Kulp²,

Span³

et al. 2009

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

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Interactions between transmembrane (TM) helices play an important role in the regulation of diverse biological functions. For example, the TM helices of integrins are believed to interact heteromerically in the resting state; disruption of this interaction results in integrin activation and cellular adhesion. However, it has been difficult to demonstrate the specificity and affinity of the interaction between integrin TM helices and to relate them to the activation process. To examine integrin TM helix associations, we developed a bacterial reporter system and used it to define the sequence motif required for helix-helix interactions in the β 1 and β 3 integrin subfamilies. The helices interact in a novel three-dimensional motif, the "reciprocating large-small motif" that is also observed in the crystal structures of unrelated proteins. Modest but specific stabilization of helix associations is realized via packing of complementary small and large groups on neighboring helices. Mutations destabilizing this motif activate native, fulllength integrins. Thus, this highly conserved dissociable motif plays a vital and widespread role as an on-off switch that can integrate with other control elements during integrin activation.interaction motif | transmembrane domain

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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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The Structure of a Receptor with Two Associating Transmembrane Domains on the Cell Surface: Integrin αIIbβ3

Cited by 141 publications

References 40 publications

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

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

Consensus motif for integrin transmembrane helix association

Kindlin supports platelet integrin αIIbβ3 activation by interacting with paxillin

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