The guidance and adhesion protein FLRT2 dimerizes in cis via dual small-X3-small transmembrane motifs

Jackson, V.A.; Hermann, Julia; Tynan, Christopher J.; Rolfe, Daniel J.; Corey, Robin A.; Duncan, Anna L.; Noriega, Maxime; Chu, Amy; Kalli, Antreas C.; Jones, E Y; Sansom, Mark S.P.; Martin-Fernandez, Marisa L.; Seiradake, E.; Chavent, Matthieu

doi:10.1016/j.str.2022.05.014

Cited by 6 publications

(5 citation statements)

References 98 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…presence of cholesterol. 32,33 However, in order to best compare with the experimental data on the NMR structures in DMPC/DHPC bicelles and some in DPC, we chose the same DMPC bilayer throughout. Each system was then run in quadruplicate for 4 µs each.…”

Section: Resultsmentioning

confidence: 99%

“…Several studies also suggested that the lipid environment and also presence of cholesterol may control the mode of dimerization. 17,20,32,33,51 For example, it is known that negatively charged lipids, such as POPS and cell signalling lipids PIP2 and PIP3 alter the functional behavior of TM-but also TM peripheral proteins cells. 53,55,56 Specifically, it is noticeable that almost all of the 11 systems chosen here contain a cationic "plug" to prevent sliding of the C-terminal region into the membrane and recent work by Barerra and colleagues 31 suggests that EphA2 may switch from a parallel TM helix dimer in a wider membrane with PIP2, where positive charges can be tolerated to the structure with a wider crossing angle in a thinner membrane without PIP2, where the juxtamembrane regions may repulse.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Transmembrane region dimer structures of Type 1 receptors readily sample alternate configurations: MD simulations using the Martini 3 coarse grained model compared to AlphaFold2 Multimer

Sahoo

Souza

Meng

et al. 2021

Preprint

View full text Add to dashboard Cite

Determination of the structure and dynamics of transmembrane (TM) domains of single-transmembrane receptors is key to understanding their mechanism of signal transduction across the plasma membrane. Although many studies have been performed on isolated soluble extra- and intracellular receptor domains in aqueous solutions, limited knowledge exists on the lipid embedded TM region. In this study, we predict the assembly of alternate configurations of receptor TM domain dimers using the Martini 3 force field for coarse-grain (CG) molecular dynamic simulations. This recent version of Martini has new bead types and sizes, which allows more accurate predictions of molecular packing and interactions compared to the previous version. Our results with Martini 3 simulations show overall good agreement with ab initio predictions using PREDDIMER and with available NMR derived structures for TM helix dimers. Understanding and predicting the association TM domains may help us to better understand the signalling mechanism of TM receptors, in turn providing the opportunity for development of new pharmaceuticals, some of which are peptide based.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Transmembrane region dimer structures of Type 1 receptors readily sample alternate configurations: MD simulations using the Martini 3 coarse grained model compared to AlphaFold2 Multimer

Sahoo

Souza

Meng

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Next to experiments of biophysics or cellular biology, CG simulations with Martini 2 or 3 have been widely used to predict TM-TM helix dimerization (or higher order oligomerization), for example in recent works [92, 93, 94, 95]. Both force field versions are able to predict TM-TM interfaces, but Martini 2 has a tendency to overaggregate TM segments.…”

Section: Discussionmentioning

confidence: 99%

Lys716 in the transmembrane domain of yeast mitofusin Fzo1 modulates anchoring and fusion

Versini,

Baaden,

Cavellini

et al. 2023

Preprint

View full text Add to dashboard Cite

Outer mitochondrial membrane (OMM) fusion is an important process for the cell and organism survival, as its dysfunction is linked to neurodegenerative diseases and cancer. The OMM fusion is mediated by members of the dynamin-related protein (DRP) family, named mitofusins. The exact mechanism by which the mitofusins contribute to these diseases, as well as the exact molecular fusion mechanism mediated by mitofusin, remains elusive. We have performed extensive multiscale molecular dynamics simulations using both coarse-grained and all-atom approaches to predict the dimerization of two transmembrane domain (TM) helices of the yeast mitofusin Fzo1. We identify specific residues, such as Lys716, that can modulate dimer stability. Comparison with a previous computational model reveals remarkable differences in helix crossing angles and interfacial contacts. Overall, however, the TM1-TM2 interface appears to be stable in the Martini and CHARMM force fields. Replica-exchange simulations further tune a detailed atomistic model, as confirmed by a remarkable agreement with an independent prediction of the Fzo1-Ugo1 complex by AlphaFold2. Functional implications, including a possible role of Lys716 that could affect membrane interactions during fusion, are suggested and consistent with experiments monitoring mitochondrial respiration of selected Fzo1 mutants.

show abstract

“…55 Simulations were analyzed using Tcl/VMD and python scripts. Protein-Ca 2+ /Na + or protein-TDB contacts and were calculated as described previously 42,66 using cutoff value of 5 Å. Occupancy of Ca 2+ and Na + ions were calculated using a cutoff of 3 Å because of the proximity between site 1 and 2.…”

Section: Methodsmentioning

confidence: 99%

“…1C). We employed free energy perturbation (FEP) calculations 42,43 to further characterize the positioning of the acyl chain of TDB inside the hydrophobic groove as a case study of soluble protein-glycolipid interactions.…”

Section: Introductionmentioning

confidence: 99%

Coarse-graining the recognition of a glycolipid by the C-type lectin Mincle receptor

Noriega,

Corey,

Haanappel

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

Macrophage inducible Ca2+-dependent lectin (Mincle) receptor recognizes Mycobacterium tuberculosis glycolipids to trigger an immune response. This host membrane receptor is thus a key player in the modulation of the immune response to infection by M. tuberculosis, and has emerged as a promising target for the development of new vaccines for tuberculosis. The recent development of the Martini 3 force field for coarse-grained (CG) molecular modeling allow the study of interactions of soluble proteins with small ligands but its use for the study of interactions with lipids remains less explored. Here, we present a refined approach detailing a protocol for modeling such interactions at a CG level using the Martini 3 force field. Using this approach, we studied Mincle and identified critical parameters governing ligand recognition, such as loop flexibility and the regulation of hydrophobic groove formation by calcium ions. In addition, we assessed ligand affinity using free energy perturbation calculations. Our results offer mechanistic insight into the interactions between Mincle and glycolipids, providing a basis for rational design of molecules targeting this type of membrane receptors.

show abstract

The guidance and adhesion protein FLRT2 dimerizes in cis via dual small-X3-small transmembrane motifs

Cited by 6 publications

References 98 publications

Transmembrane region dimer structures of Type 1 receptors readily sample alternate configurations: MD simulations using the Martini 3 coarse grained model compared to AlphaFold2 Multimer

Transmembrane region dimer structures of Type 1 receptors readily sample alternate configurations: MD simulations using the Martini 3 coarse grained model compared to AlphaFold2 Multimer

Lys716 in the transmembrane domain of yeast mitofusin Fzo1 modulates anchoring and fusion

Coarse-graining the recognition of a glycolipid by the C-type lectin Mincle receptor

Contact Info

Product

Resources

About