Transmembrane Domain Helix Packing Stabilizes Integrin αIIbβ3 in the Low Affinity State

Partridge, Anthony W.; Liu, Shouchun; Kim, Sanguk; Bowie, James U.; Ginsberg, Mark H.

doi:10.1074/jbc.m412701200

Cited by 141 publications

(171 citation statements)

References 39 publications

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“…However, recent work has clearly identified signalling molecules that associate with integrins. Many studies have focused on the short cytoplasmic tails and the transmembrane domains of the integrin α and β subunits (Box 1, panel a), which may have applications in future anti-integrin strategies [103][104][105] .…”

Section: Integrin Signallingmentioning

confidence: 99%

See 1 more Smart Citation

Integrins as therapeutic targets: lessons and opportunities

Cox

Brennan

Moran

2010

Nat Rev Drug Discov

404

350

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Section: Integrin Signallingmentioning

confidence: 99%

“…Potential strategies are focused on the short cytoplasmic tails of the integrin α and β subunits, although there is also evidence that the transmembrane domains may play a role [103][104]166 .…”

Section: Receptor Antagonists That Do Not Induce Conformational Changmentioning

confidence: 99%

Integrins as therapeutic targets: lessons and opportunities

Cox

Brennan

Moran

2010

Nat Rev Drug Discov

404

350

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“…While these mutations have been previously shown to activate the receptor (11,14,34), a systematic quantitative comparison of their individual effects and their combination has not been considered. Fig.…”

Section: Correlation Of the Tmcd Interface With Integrin Mutation Datmentioning

confidence: 99%

“…Biochemical and structural evidence suggests that the ␣/␤ TMCDs associate via both their TMs (3)(4)(5)(6) and their CTs (7)(8)(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).…”

mentioning

confidence: 99%

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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“…This approach has not been so widely used for GPCRs [34]. The main constraint is that GPCRs are resistant to complete denaturation, i.e.…”

Section: Conformational Stability Of Gpcrsmentioning

confidence: 99%

Stabilization of Membrane Proteins: the Case of G‐Protein‐Coupled Receptors

Reyes‐Alcaraz

Tzanov

Garriga

2008

Engineering in Life Sciences

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G-protein-coupled receptors are integral membrane proteins which constitute the largest family of signal transduction molecules participating in the majority of normal physiological processes. G-protein-coupled receptors are responsible for the control of enzyme activity, ion channels and vesicle transport, and they respond to a wide variety of stimuli, like signals involved in sensory systems such as vision, taste and olfaction, but also to a diverse set of chemical signals such as lipids, hormones, neurotransmitters, amino acids, nucleotides, peptides and proteins. This family of receptors is being widely studied because of its potential use as pharmacological targets in drug development, and recently also for its potential use in the development of novel biosensors. G-protein-coupled receptors are specifically designed to fold and function in a lipid bilayer environment, where these membrane proteins are remarkably stable and achieve their optimal performance. The currently used technology for the purification of G-protein-coupled receptors consists in their extraction from the cell membrane and solubilization into detergent micelles. A common drawback of this strategy is that G-proteincoupled receptors solubilized in typical detergents show rather poor conformational stability, which may result in relatively rapid inactivation. The poor stability of detergent-solubilized samples renders many membrane proteins biochemically intractable. This precludes the determination of a high-resolution structure and imposes severe limitations for the development of applications. Thus, the enhancement of the stability of G-protein-coupled receptors is a major issue in order to facilitate structural determination and to unravel their potential in biotechnological applications. This work provides a brief overview of some current advances in the experimental methods for stabilizing G-protein-coupled receptors that can also be extended to other types of membrane proteins. Structure of G-protein-Coupled Receptors (GPCRs)The distinctive structural feature of GPCRs is the bundle of seven transmembrane (7TM) a-helices that constitutes a relevant signature in structural biology. This conformational architecture, and its functional implications, is central to pharmacology and therapeutics. Nearly 2000 GPCRs have been reported since bovine opsin was cloned in 1983 and the b-adrenergic receptor in 1986. They are classified into over 100 subfamilies as a function of their sequence homology, ligand structure and receptor function. Significant differences exist among the members of the GPCRs superfamily, in spite of the high degree of amino acid homology found among the members of a particular subfamily. The visual photoreceptor rhodopsin (Rho) was the first GPCR whose crystal structure was determined at high-resolution [1][2][3][4][5][6][7]. The natural abundance and availability of Rho has made of this protein the prototypical GPCR for structural studies. As a consequence, Rho is often selected as a model protein for biochemical and b...

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Transmembrane Domain Helix Packing Stabilizes Integrin αIIbβ3 in the Low Affinity State

Cited by 141 publications

References 39 publications

Integrins as therapeutic targets: lessons and opportunities

Integrins as therapeutic targets: lessons and opportunities

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

Stabilization of Membrane Proteins: the Case of G‐Protein‐Coupled Receptors

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