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Hydrophobic matching controls the tilt and stability of the dimeric platelet-derived growth factor receptor (PDGFR) β transmembrane segment.

Muhle-Goll C, Hoffmann S, Afonin S, Grage SL, Polyansky AA, Windisch D, Zeitler M, Bürck J, Ulrich AS
J Biol Chem 287 26178-86 (2012)
Cited: 36 times
EuropePMC logo PMID: 22619173

Abstract

The platelet-derived growth factor receptor β is a member of the cell surface receptor tyrosine kinase family and dimerizes upon activation. We determined the structure of the transmembrane segment in dodecylphosphocholine micelles by liquid-state NMR and found that it forms a stable left-handed helical dimer. Solid-state NMR and oriented circular dichroism were used to measure the tilt angle of the helical segments in macroscopically aligned model membranes with different acyl chain lengths. Both methods showed that decreasing bilayer thickness (DEPC-POPC-DMPC) led to an increase in the helix tilt angle from 10° to 30° with respect to the bilayer normal. At the same time, reconstitution of the comparatively long hydrophobic segment became less effective, eventually resulting in complete protein aggregation in the short-chain lipid DLPC. Unrestrained molecular dynamics simulations of the dimer were carried out in explicit lipid bilayers (DEPC, POPC, DMPC, sphingomyelin), confirming the observed dependence of the helix tilt angle on bilayer thickness. Notably, molecular dynamics revealed that the left-handed dimer gets tilted en bloc, whereas conformational transitions to alternative (e.g. right-handed dimeric) states were not supported. The experimental data along with the simulation results demonstrate a pronounced interplay between the platelet-directed growth factor receptor β transmembrane segment and the bilayer thickness. The effect of hydrophobic mismatch might play a key role in the redistribution and activation of the receptor within different lipid microdomains of the plasma membrane in vivo.

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Articles - 2l6w mentioned but not cited (7)

  1. Hydrophobic matching controls the tilt and stability of the dimeric platelet-derived growth factor receptor (PDGFR) β transmembrane segment. Muhle-Goll C, Hoffmann S, Afonin S, Grage SL, Polyansky AA, Windisch D, Zeitler M, Bürck J, Ulrich AS. J. Biol. Chem. 287 26178-26186 (2012)
  2. Evolutionary-guided de novo structure prediction of self-associated transmembrane helical proteins with near-atomic accuracy. Wang Y, Barth P. Nat Commun 6 7196 (2015)
  3. Dimerization of the EphA1 receptor tyrosine kinase transmembrane domain: Insights into the mechanism of receptor activation. Chavent M, Chetwynd AP, Stansfeld PJ, Sansom MS. Biochemistry 53 6641-6652 (2014)
  4. A lipophilicity-based energy function for membrane-protein modelling and design. Weinstein JY, Elazar A, Fleishman SJ. PLoS Comput Biol 15 e1007318 (2019)
  5. The dipeptidyl peptidase IV inhibitors vildagliptin and K-579 inhibit a phospholipase C: a case of promiscuous scaffolds in proteins. Chakraborty S, Rendón-Ramírez A, Ásgeirsson B, Dutta M, Ghosh AS, Oda M, Venkatramani R, Rao BJ, Dandekar AM, Goñi FM. F1000Res 2 286 (2013)
  6. Experimental determination and data-driven prediction of homotypic transmembrane domain interfaces. Xiao Y, Zeng B, Berner N, Frishman D, Langosch D, Teese MG. Comput Struct Biotechnol J 18 3230-3242 (2020)
  7. Amino Acid Conjugates of Aminothiazole and Aminopyridine as Potential Anticancer Agents: Synthesis, Molecular Docking and in vitro Evaluation. Naz S, Shah FA, Nadeem H, Sarwar S, Tan Z, Imran M, Ali T, Li JB, Li S. Drug Des Devel Ther 15 1459-1476 (2021)


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  3. Solid-state NMR spectroscopy to study protein-lipid interactions. Huster D. Biochim. Biophys. Acta 1841 1146-1160 (2014)
  4. Analytical Techniques in Lipidomics: State of the Art. Jurowski K, Kochan K, Walczak J, Barańska M, Piekoszewski W, Buszewski B. Crit Rev Anal Chem 47 418-437 (2017)
  5. Understanding single-pass transmembrane receptor signaling from a structural viewpoint-what are we missing? Bugge K, Lindorff-Larsen K, Kragelund BB. FEBS J. 283 4424-4451 (2016)
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  2. Conformational Changes in the Epidermal Growth Factor Receptor: Role of the Transmembrane Domain Investigated by Coarse-Grained MetaDynamics Free Energy Calculations. Lelimousin M, Limongelli V, Sansom MS. J. Am. Chem. Soc. 138 10611-10622 (2016)
  3. 3D hydrophobic moment vectors as a tool to characterize the surface polarity of amphiphilic peptides. Reißer S, Strandberg E, Steinbrecher T, Ulrich AS. Biophys. J. 106 2385-2394 (2014)
  4. Dynamical structure of the short multifunctional peptide BP100 in membranes. Wadhwani P, Strandberg E, van den Berg J, Mink C, Bürck J, Ciriello RA, Ulrich AS. Biochim. Biophys. Acta 1838 940-949 (2014)
  5. A coiled coil switch mediates cold sensing by the thermosensory protein DesK. Saita E, Abriata LA, Tsai YT, Trajtenberg F, Lemmin T, Buschiazzo A, Dal Peraro M, de Mendoza D, Albanesi D. Mol. Microbiol. 98 258-271 (2015)
  6. Structure of Full-Length Human PDGFRβ Bound to Its Activating Ligand PDGF-B as Determined by Negative-Stain Electron Microscopy. Chen PH, Unger V, He X. J. Mol. Biol. 427 3921-3934 (2015)
  7. Small-size platelet microparticles trigger platelet and monocyte functionality and modulate thrombogenesis via P-selectin. Montoro-García S, Shantsila E, Hernández-Romero D, Jover E, Valdés M, Marín F, Lip GY. Br. J. Haematol. 166 571-580 (2014)
  8. Action of the multifunctional peptide BP100 on native biomembranes examined by solid-state NMR. Misiewicz J, Afonin S, Grage SL, van den Berg J, Strandberg E, Wadhwani P, Ulrich AS. J. Biomol. NMR 61 287-298 (2015)
  9. Active S2168 and inactive S21IRS pinholin interact differently with the lipid bilayer: A 31P and 2H solid state NMR study. Drew DL, Butcher B, Sahu ID, Ahammad T, Dixit G, Lorigan GA. Biochim Biophys Acta Biomembr 1862 183257 (2020)
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  11. Hydrophobic Mismatch Drives the Interaction of E5 with the Transmembrane Segment of PDGF Receptor. Windisch D, Ziegler C, Grage SL, Bürck J, Zeitler M, Gor'kov PL, Ulrich AS. Biophys. J. 109 737-749 (2015)
  12. Length matters: Functional flip of the short TatA transmembrane helix. Stockwald ER, Steger LME, Vollmer S, Gottselig C, Grage SL, Bürck J, Afonin S, Fröbel J, Blümmel AS, Setzler J, Wenzel W, Walther TH, Ulrich AS. Biophys J 122 2125-2146 (2023)
  13. Mechanism of Allosteric Coupling into and through the Plasma Membrane by EGFR. Sinclair JKL, Walker AS, Doerner AE, Schepartz A. Cell Chem Biol 25 857-870.e7 (2018)
  14. Two transmembrane dimers of the bovine papillomavirus E5 oncoprotein clamp the PDGF β receptor in an active dimeric conformation. Karabadzhak AG, Petti LM, Barrera FN, Edwards APB, Moya-Rodríguez A, Polikanov YS, Freites JA, Tobias DJ, Engelman DM, DiMaio D. Proc. Natl. Acad. Sci. U.S.A. 114 E7262-E7271 (2017)
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  16. Orthogonal 19 F-Labeling for Solid-State NMR Spectroscopy Reveals the Conformation and Orientation of Short Peptaibols in Membranes. Grage SL, Kara S, Bordessa A, Doan V, Rizzolo F, Putzu M, Kubař T, Papini AM, Chaume G, Brigaud T, Afonin S, Ulrich AS. Chemistry 24 4328-4335 (2018)
  17. SARS-CoV-2 antigen-carrying extracellular vesicles activate T cell responses in a human immunogenicity model. Cummings SE, Delaney SP, St-Denis Bissonnette F, Stalker A, Muradia G, Mehic J, Graber TE, Alain T, Lavoie JR. iScience 27 108708 (2024)
  18. Structural and functional characterization of the pore-forming domain of pinholin S2168. Steger LME, Kohlmeyer A, Wadhwani P, Bürck J, Strandberg E, Reichert J, Grage SL, Afonin S, Kempfer M, Görner AC, Koch J, Walther TH, Ulrich AS. Proc Natl Acad Sci U S A 117 29637-29646 (2020)
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  20. The role of hydrophobic matching on transmembrane helix packing in cells. Grau B, Javanainen M, García-Murria MJ, Kulig W, Vattulainen I, Mingarro I, Martínez-Gil L. Cell Stress 1 90-106 (2017)


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