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

Kalli, Antreas C.; Hall, Benjamin A.; Campbell, Iain D.; Sansom, Mark S. P.

doi:10.1016/j.str.2011.07.014

Cited by 37 publications

(41 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We carried out large-scale CG MD simulations on the MSDesK sequence with the Martini 2.2 force field (27) and standard Martini settings in GROMACS 4.5.x (28). Martini is a widely used CG force field (29), and this type of approach has been proven successful in modeling helix-helix interactions in membrane environments (21,(30)(31)(32)(33)(34). Here we used a recently developed high-throughput method, the docking assay for transmembrane components (DAFT) (35), to screen MS-TMS dimers.…”

Section: Discussionmentioning

confidence: 99%

Activation of the bacterial thermosensor DesK involves a serine zipper dimerization motif that is modulated by bilayer thickness

Cybulski¹,

Ballering

Moussatova

et al. 2015

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

View full text Add to dashboard Cite

DesK is a bacterial thermosensor protein involved in maintaining membrane fluidity in response to changes in environmental temperature. Most likely, the protein is activated by changes in membrane thickness, but the molecular mechanism of sensing and signaling is still poorly understood. Here we aimed to elucidate the mode of action of DesK by studying the so-called "minimal sensor DesK" (MS-DesK), in which sensing and signaling are captured in a single transmembrane segment. This simplified version of the sensor allows investigation of membrane thickness-dependent protein-lipid interactions simply by using synthetic peptides, corresponding to the membrane-spanning parts of functional and nonfunctional mutants of MS-DesK incorporated in lipid bilayers with varying thicknesses. The lipid-dependent behavior of the peptides was investigated by circular dichroism, tryptophan fluorescence, and molecular modeling. These experiments were complemented with in vivo functional studies on MS-DesK mutants. Based on the results, we constructed a model that suggests a new mechanism for sensing in which the protein is present as a dimer and responds to an increase in bilayer thickness by membrane incorporation of a C-terminal hydrophilic motif. This results in exposure of three serines on the same side of the transmembrane helices of MS-DesK, triggering a switching of the dimerization interface to allow the formation of a serine zipper. The final result is activation of the kinase state of MS-DesK.thermosensing | two-component system | lipid-protein interaction | helix-helix interaction | transmembrane helix dimerization

show abstract

Section: Discussionmentioning

confidence: 99%

Activation of the bacterial thermosensor DesK involves a serine zipper dimerization motif that is modulated by bilayer thickness

Cybulski¹,

Ballering

Moussatova

et al. 2015

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

View full text Add to dashboard Cite

show abstract

“…For reference, the stability of the mutant ␣IIb(R995A)␤3 TM complex is similar to the TM complex stability of the fibroblast growth factor receptor 3 at Ϫ2.8 Ϯ 0.1 kcal/mol (51 ) contacts were compared in MD simulations of 100-ns duration. The suitability of MD simulations for studying the ␣IIb␤3 TM complex is well established (52). The TM complex was examined in the presence of POPC and POPS bilayers starting with engaged and disengaged ␣IIb(Arg 995 )-␤3(Asp 723 ) contact, respectively.…”

Section: Anionic Lipids Stabilize the ␣Iib␤3 Tm Complex Relative Tomentioning

confidence: 99%

Annular Anionic Lipids Stabilize the Integrin αIIbβ3 Transmembrane Complex

Schmidt

Suk

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…23 Molecular simulations are being increasingly used to understand the molecular basis of several membrane processes, including membrane-protein association. 24 A wide range of models, such as atomistic, 8,[25][26][27][28] coarse-grain 7,[29][30][31][32][33] and lower resolution models, [34][35][36][37] have been used to probe transmembrane helix association. Quantitative analysis of transmembrane helix association by the calculation of the potential of mean force (PMF) along the inter-helical distance has shown similar profiles for several single transmembrane helix dimers.…”

Section: Introductionmentioning

confidence: 99%

Thermodynamic and kinetic characterization of transmembrane helix association

Pawar

Deshpande

Gopal

et al. 2015

Phys. Chem. Chem. Phys.

View full text Add to dashboard Cite

The transient dimerization of transmembrane proteins is an important event in several cellular processes and computational methods are being increasingly used to quantify their underlying energetics. Here, we probe the thermodynamics and kinetics of a simple transmembrane dimer to understand membrane protein association. A multi-step framework has been developed in which the dimerization profiles are calculated from coarse-grain molecular dynamics simulations, followed by meso-scale simulations using parameters calculated from the coarse-grain model. The calculated value of DG assoc is approx. À20 kJ mol À1 and is consistent between three methods. Interestingly, the meso-scale stochastic model reveals low dimer percentages at physiologically-relevant concentrations, despite a favorable DG assoc . We identify generic driving forces arising from the protein backbone and lipid bilayer and complementary factors, such as protein density, that govern self-interactions in membranes. Our results provide an important contribution in understanding membrane protein organization and linking molecular, nano-scale computational studies to meso-scale experimental data.

show abstract

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

Cited by 37 publications

References 65 publications

Activation of the bacterial thermosensor DesK involves a serine zipper dimerization motif that is modulated by bilayer thickness

Activation of the bacterial thermosensor DesK involves a serine zipper dimerization motif that is modulated by bilayer thickness

Annular Anionic Lipids Stabilize the Integrin αIIbβ3 Transmembrane Complex

Thermodynamic and kinetic characterization of transmembrane helix association

Contact Info

Product

Resources

About