A Transmembrane Polar Interaction Is Involved in the Functional Regulation of Integrin αLβ2

Vararattanavech, Ardcharaporn; Chng, Choon-Peng; Parthasarathy, Krupakar; Tang, Xiaoyan; Torres, Jaume; Tan, Suet-Mien

doi:10.1016/j.jmb.2010.03.027

Cited by 15 publications

(35 citation statements)

References 69 publications

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“…In αL, a polar residue, Ser-1071, was hypothesized to form a polar interaction with Thr-686 at the binding partner β2 [36]. Both the alignment of Ser-1071 with Gly-1075 and the hydrophobic IMC region, together with the sensitivity of these residues to titration with the β2 peptide, are consistent with this part of αL forming a polar interaction with β2.…”

Section: Discussionmentioning

confidence: 95%

“…The importance of the GFFKR motif in αL has been demonstrated by looking at the effect of deletion of this motif in a transgenic mouse, which led to a constitutive αLβ2-mediated cell adhesion [35]. Additionally, in these fast-migrating cells, integrin deactivation is particularly important, and we proposed previously that the latter could be facilitated by hydrogen bond interaction between TMs [36]–[38]. Thus, to elucidate if the reverse turn at the GFFKR motif is also found in αL when the peptide is reconstituted in bicelles, and to delineate the αL interfacial residues involved in αL/β2 interaction, we have expressed, purified and determined the structure of αL TM in bicelles by solution NMR.…”

Section: Introductionmentioning

confidence: 97%

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Transmembrane and Juxtamembrane Structure of αL Integrin in Bicelles

Surya

Millet

et al. 2013

PLoS ONE

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The accepted model for the interaction of α and β integrins in the transmembrane (TM) domain is based on the pair αIIbβ3. This involves the so-called outer and inner membrane association clasps (OMC and IMC, respectively). In the α chain, the OMC involves a GxxxG-like motif, whereas in the IMC a conserved juxtamembrane GFFKR motif experiences a backbone reversal that partially fills the void generated by TM separation towards the cytoplasmic half. However, the GFFKR motif of several α integrin cytoplasmic tails in non-bicelle environments has been shown to adopt an α-helical structure that is not membrane-embedded and which was shown to bind a variety of cytoplasmic proteins. Thus it is not known if a membrane-embedded backbone reversal is a conserved structural feature in α integrins. We have studied the system αLβ2 because of its importance in leukocytes, where integrin deactivation is particularly important. Herein we show that the backbone reversal feature is not only present in αIIb but also in αL-TM when reconstituted in bicelles. Additionally, titration with β2 TM showed eight residues clustering along one side of αL-TM, forming a plausible interacting face with β2. The latter orientation is consistent with a previously predicted reported polar interaction between αL Ser-1071 and β2 Thr-686.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 97%

Transmembrane and Juxtamembrane Structure of αL Integrin in Bicelles

Surya

Millet

et al. 2013

PLoS ONE

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“…Besides the αIIb/β3 heterodimer, recent studies (Chng and Tan, 2011; Vararattanavech et al., 2010) for the TM region of the αLβ2 integrin suggest similar packing to that seen in our studies for the helices in the outer membrane clasp (OMC) region (because of the presence of a GxxxG-like motif, i.e., SxxxG). This, in combination with the fact that sequence alignment of the different integrin α subunits reveals the presence of a small-xxx-small motif in many integrin α subunits, suggest that this is a general property of integrins (Vararattanavech et al., 2010). In addition, experimental (Lau et al., 2009; Li et al., 2005; Yang et al., 2009) and computational (Kalli et al., 2011) data suggest that disruption of OMC interactions is a key step in switching integrins from an inactive to an active state.…”

Section: Discussionmentioning

confidence: 98%

A Helix Heterodimer in a Lipid Bilayer: Prediction of the Structure of an Integrin Transmembrane Domain via Multiscale Simulations

et al. 2011

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SummaryDimerization of transmembrane (TM) α helices of membrane receptors plays a key role in signaling. We show that molecular dynamics simulations yield models of integrin TM helix heterodimers, which agree well with available NMR structures. We use a multiscale simulation approach, combining coarse-grained and subsequent atomistic simulation, to model the dimerization of wild-type (WT) and mutated sequences of the αIIb and β3 integrin TM helices. The WT helices formed a stable, right-handed dimer with the same helix-helix interface as in the published NMR structure (PDB: 2K9J). In contrast, the presence of disruptive mutations perturbed the interface between the helices, altering the conformational stability of the dimer. The αIIb/β3 interface was more flexible than that of, e.g., glycophorin A. This is suggestive of a role for alternative packing modes of the TM helices in transbilayer signaling.

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“…The association affinity of the α and β TM regions that constitute the OMC could vary amongst integrins because of sequence variation [12]. Indeed, a polar interaction between αLSer 1096 and β2Thr 708 in the integrin αLβ2 OMC, which is absent from the integrin αIIbβ3 OMC, plays an important role in the packing of the αLβ2 TM helices [42]. The TM-TM association free energy profiles of the αLβ2 and αIIbβ3 integrins are also different [43].…”

Section: Introductionmentioning

confidence: 99%

The leucocyte β2 (CD18) integrins: the structure, functional regulation and signalling properties

2012

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Leucocytes are highly motile cells. Their ability to migrate into tissues and organs is dependent on cell adhesion molecules. The integrins are a family of heterodimeric transmembrane cell adhesion molecules that are also signalling receptors. They are involved in many biological processes, including the development of metazoans, immunity, haemostasis, wound healing and cell survival, proliferation and differentiation. The leucocyte-restricted β2 integrins comprise four members, namely αLβ2, αMβ2, αXβ2 and αDβ2, which are required for a functional immune system. In this paper, the structure, functional regulation and signalling properties of these integrins are reviewed.

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A Transmembrane Polar Interaction Is Involved in the Functional Regulation of Integrin αLβ2

Cited by 15 publications

References 69 publications

Transmembrane and Juxtamembrane Structure of αL Integrin in Bicelles

Transmembrane and Juxtamembrane Structure of αL Integrin in Bicelles

A Helix Heterodimer in a Lipid Bilayer: Prediction of the Structure of an Integrin Transmembrane Domain via Multiscale Simulations

The leucocyte β2 (CD18) integrins: the structure, functional regulation and signalling properties

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