Structure of the Integrin αIIb Transmembrane Segment

Tong-Lay Lau,Varun Dua,Tobias S Ulmer

doi:10.1074/jbc.m801748200

Tong-Lay Lau, Varun Dua + Show 1 more

Open Access

https://doi.org/10.1074/jbc.m801748200

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Abstract

Integrin cell-adhesion receptors transduce signals bidirectionally across the plasma membrane via the single-pass transmembrane segments of each alpha and beta subunit. While the beta3 transmembrane segment consists of a linear 29-residue alpha-helix, the structure of the alphaIIb transmembrane segment reveals a linear 24-residue alpha-helix (Ile-966 -Lys-989) followed by a backbone reversal that packs Phe-992-Phe-993 against the transmembrane helix. The length of the alphaIIb transmembrane helix implies the absence of a significant transmembrane helix tilt in contrast to its partnering beta3 subunit. Sequence alignment shows Gly-991-Phe-993 to be fully conserved among all 18 human integrin alpha subunits, suggesting that their unusual structural motif is prototypical for integrin alpha subunits. The alphaIIb transmembrane structure demonstrates a level of complexity within the membrane that is beyond simple transmembrane helices and forms the structural basis for assessing the extent of structural and topological rearrangements upon alphaIIb-beta3 association, i.e. integrin transmembrane signaling.

Highlights

Integrins are a major class of adhesion receptors that mediate cell migration and extracellular matrix assembly, as well as inflammation, thrombosis, and tumor metastasis [1]
In addition to responding to signals that originate inside the cell and regulate receptor affinity, integrins can respond to the binding of extracellular ligands by activating intracellular signaling pathways [1]
The inactive receptor state is stabilized by the hydrophobic packing of the TM helices and adjacent electrostatic ␣IIb-␤3 interactions, whereas integrin activation ensues from the separation of the TM segments (2, 4 – 8)

Summary

Introduction

Integrins are a major class of adhesion receptors that mediate cell migration and extracellular matrix assembly, as well as inflammation, thrombosis, and tumor metastasis [1]. The recently determined structure of the integrin ␤3 TM segment reconstituted in small bicelles fulfills this expectation, but the TM helix is not restricted to residues between the first charged residues, Asp-692 and Lys-716, on the extraand intracellular sides, respectively [9]. The structure of the ␣IIb TM segment reported shows that the TM helix ends at Lys-989 and that the following four residues loop back to immerse Phe-992–Phe-993 in the hydrophobic lipid core.

Results

Conclusion