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A helix heterodimer in a lipid bilayer: prediction of the structure of an integrin transmembrane domain via multiscale simulations.

ABSTRACT: Dimerization of transmembrane (TM) ? 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 ?IIb and ?3 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 ?IIb/?3 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.

SUBMITTER: Kalli AC

PROVIDER: S-EPMC3195670 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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A helix heterodimer in a lipid bilayer: prediction of the structure of an integrin transmembrane domain via multiscale simulations.

Kalli Antreas C AC Hall Benjamin A BA Campbell Iain D ID Sansom Mark S P MS

Structure (London, England : 1993) 20111001 10

Dimerization 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 wi ...[more]

PMID: 22000516

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Project description:Integrins link the cytoskeleton to the extracellular matrix and regulate key signaling events that coordinate cellular processes such as secretion, migration, and proliferation. A single integrin molecule can exist in a resting state that does not bind extracellular ligands or in an active state that can engage ligands and form large signaling complexes. Activation signals are transduced between the cytosolic region and the extracellular region by a binary on/off switch in the integrin's transmembrane (TM) domain; the integrin's alpha and beta subunits each have a single TM helix that forms an alpha/beta heterodimer in the resting state, and the TM heterodimer separates to transduce an activation signal across the membrane. In this article, two methods used to generate models of the TM heterodimer, both converging on the same structure, are described. The first model was generated by a Monte Carlo algorithm that selected conformations based on their agreement with published experimental mutagenesis results. The second model was generated by threading the integrin's sequence onto TM helix dimers parsed from the Protein Data Bank and by selecting conformations based on their agreement with published experimental cysteine crosslinking results. The two models have similar structures; however, they differ markedly from some previously published models. To distinguish conformations that reflect the native integrin, we compared the Monte Carlo model, the threaded model, and four published models with experimental mutagenesis and cysteine crosslinking results. The models presented here had high correlation coefficients when compared with experimental findings, and they are in excellent agreement, both in terms of accuracy and in terms of precision, with a recent NMR structure. These results demonstrate that multiple approaches converged on the same structure of the resting integrin's TM heterodimer, and this conformation likely reflects the integrin's native structure.

Dataset Information

A helix heterodimer in a lipid bilayer: prediction of the structure of an integrin transmembrane domain via multiscale simulations.

Publications

A helix heterodimer in a lipid bilayer: prediction of the structure of an integrin transmembrane domain via multiscale simulations.

Similar Datasets

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