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Structural requirements of the extracellular to transmembrane domain junction for erythropoietin receptor function

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Kubatzky, KF [UCL] Liu, W. Goldgraben, K Simmerling, C Smith, SO Constantinescu, Stefan N. [UCL]

The erythropoietin receptor (EpoR) is crucial for erythrocyte formation. The x-ray crystal structures of the EpoR extracellular domain lack the juxtamembrane (JM) region and the junction to the transmembrane (TM) domain. Yet the JM-TM regions are important for transmitting the conformational change imposed on the receptor dimer by Epo binding. Cysteine-scanning mutagenesis of the JM-TM regions identified three novel constitutively active mutants, demonstrating close disulfide-bonded juxtapositioning of these residues in the JM (L223C) and N-terminal TM domain (L226C, I227C). Chemical cross-linking defined the interface of the active helical TM dimer and revealed that the JM-TM segment encompassing Leu(226)-Leu(230) is non-helical. Molecular dynamics and NMR studies indicated that the TM-JM junction forms an N-terminal helix cap. This structure is important for EpoR function because replacement of this motif by consecutive leucines rendered the receptor constitutively active.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès restreint
Publication date 2005
Language Anglais
Journal information "Journal of Biological Chemistry" - Vol. 280, no. 15, p. 14844-14854 (2005)
Peer reviewed yes
Publisher Amer Soc Biochemistry Molecular Biology Inc (Bethesda)
issn 0021-9258
e-issn 1083-351X
Publication status Publié
Affiliation UCL - MD/MIGE - Département de microbiologie, d'immunologie et de génétique
Links
  1. Constantinescu Stefan N, Huang Lily Jun-shen, Nam Hyung-song, Lodish Harvey F, The Erythropoietin Receptor Cytosolic Juxtamembrane Domain Contains an Essential, Precisely Oriented, Hydrophobic Motif, 10.1016/s1097-2765(01)00185-x
  2. D'Andrea Alan D., Lodish Harvey F., Wong Gordon G., Expression cloning of the murine erythropoietin receptor, 10.1016/0092-8674(89)90965-3
  3. Seubert Nadine, Royer Yohan, Staerk Judith, Kubatzky Katharina F, Moucadel Virginie, Krishnakumar Shyam, Smith Steven O, Constantinescu Stefan N, Active and Inactive Orientations of the Transmembrane and Cytosolic Domains of the Erythropoietin Receptor Dimer, 10.1016/s1097-2765(03)00389-7
  4. Constantinescu S. N., Keren T., Socolovsky M., Nam H.-s., Henis Y. I., Lodish H. F., Ligand-independent oligomerization of cell-surface erythropoietin receptor is mediated by the transmembrane domain, 10.1073/pnas.081069198
  5. Kubatzky Katharina F., Ruan Weiming, Gurezka Rolf, Cohen Jacob, Ketteler Robin, Watowich Stephanie S., Neumann Drorit, Langosch Dieter, Klingmüller Ursula, Self assembly of the transmembrane domain promotes signal transduction through the erythropoietin receptor, 10.1016/s0960-9822(01)00018-5
  6. Greiser Jens S., Stross Claudia, Heinrich Peter C., Behrmann Iris, Hermanns Heike M., Orientational Constraints of the gp130 Intracellular Juxtamembrane Domain for Signaling, 10.1074/jbc.m204113200
  7. Liu Xuedong, Constantinescu Stefan N., Sun Yin, Bogan Jonathan S., Hirsch David, Weinberg Robert A., Lodish Harvey F., Generation of Mammalian Cells Stably Expressing Multiple Genes at Predetermined Levels, 10.1006/abio.2000.4478
  8. Pear W. S., Nolan G. P., Scott M. L., Baltimore D., Production of high-titer helper-free retroviruses by transient transfection., 10.1073/pnas.90.18.8392
  9. J. Virol., 70, 5701 (1996)
  10. Huang Lily Jun-shen, Constantinescu Stefan N., Lodish Harvey F., The N-Terminal Domain of Janus Kinase 2 Is Required for Golgi Processing and Cell Surface Expression of Erythropoietin Receptor, 10.1016/s1097-2765(01)00401-4
  11. Sotiropoulos Athanassia, Moutoussamy Soraya, Binart Nadine, Kelly Paul A., Finidori Joëlle, The membrane proximal region of the cytoplasmic domain of the growth hormone receptor is involved in the activation of Stat 3, 10.1016/0014-5793(95)00734-q
  12. Metz G., Wu X.L., Smith S.O., Ramped-Amplitude Cross Polarization in Magic-Angle-Spinning NMR, 10.1006/jmra.1994.1208
  13. Wu Hong, Liu Xin, Jaenisch Rudolf, Lodish Harvey F., Generation of committed erythroid BFU-E and CFU-E progenitors does not require erythropoietin or the erythropoietin receptor, 10.1016/0092-8674(95)90234-1
  14. Bennett Andrew E., Rienstra Chad M., Auger Michèle, Lakshmi K. V., Griffin Robert G., Heteronuclear decoupling in rotating solids, 10.1063/1.470372
  15. Simmerling Carlos, Strockbine Bentley, Roitberg Adrian E., All-Atom Structure Prediction and Folding Simulations of a Stable Protein, 10.1021/ja0273851
  16. Case, D. A., Pearlman, D. A., Caldwell, J. A., Cheatham, T. E., Wang, J., Ross, W. S., Simmerling, C. L., Darden, T. A., Merz, K. M., Stanton, R. V., Cheng, A. L., Vincent, J. J., Crowley, M., Tsui, V., Gohlke, H., Radmer, R. J., Duan, Y., Pitera, J., Massova, I., Seibel, G. L., Singh, U. C., Weiner, P. K., and Kollman, P. A. (2002) AMBER 7 User's Manual, University of California, San Francisco
  17. Still W. Clark, Tempczyk Anna, Hawley Ronald C., Hendrickson Thomas, Semianalytical treatment of solvation for molecular mechanics and dynamics, 10.1021/ja00172a038
  18. Tsui Vickie, Case David A., Theory and applications of the generalized born solvation model in macromolecular simulations, 10.1002/1097-0282(2000)56:4<275::aid-bip10024>3.0.co;2-e
  19. Falke J., Koshland D., Global flexibility in a sensory receptor: a site-directed cross-linking approach, 10.1126/science.2820061
  20. J. Biol. Chem., 269, 29920 (1994)
  21. Loo Tip W., Clarke David M., Membrane Topology of a Cysteine-less Mutant of Human P-glycoprotein, 10.1074/jbc.270.2.843
  22. Yoshimura Akihiko, Longmore Gregory, Lodish Harvey F., Point mutation in the exoplasmic domain of the erythropoietin receptor resulting in hormone-independent activation and tumorigenicity, 10.1038/348647a0
  23. Watowich S. S., Yoshimura A., Longmore G. D., Hilton D. J., Yoshimura Y., Lodish H. F., Homodimerization and constitutive activation of the erythropoietin receptor., 10.1073/pnas.89.6.2140
  24. Constantinescu Stefan N., Ghaffari Saghi, Lodish Harvey F., The Erythropoietin Receptor: Structure, Activation and Intracellular Signal Transduction, 10.1016/s1043-2760(98)00101-5
  25. Klingmuller U., Bergelson S., Hsiao J. G., Lodish H. F., Multiple tyrosine residues in the cytosolic domain of the erythropoietin receptor promote activation of STAT5., 10.1073/pnas.93.16.8324
  26. Zang H., The distal region and receptor tyrosines of the Epo receptor are non-essential for in vivo erythropoiesis, 10.1093/emboj/20.12.3156
  27. Palacios Ronald, Steinmetz Michael, IL3-dependent mouse clones that express B-220 surface antigen, contain ig genes in germ-line configuration, and generate B lymphocytes in vivo, 10.1016/s0092-8674(85)80053-2
  28. Watowich S S, Hilton D J, Lodish H F, Activation and inhibition of erythropoietin receptor function: role of receptor dimerization., 10.1128/mcb.14.6.3535
  29. Burke Christine L., Stern David F., Activation of Neu (ErbB-2) Mediated by Disulfide Bond-Induced Dimerization Reveals a Receptor Tyrosine Kinase Dimer Interface, 10.1128/mcb.18.9.5371
  30. Miura O., Ihle J.N., Dimer- and Oligomerization of the Erythropoietin Receptor by Disulfide Bond Formation and Significance of the Region Near the WSXWS Motif in Intracellular Transport, 10.1006/abbi.1993.1501
  31. Green Nora S., Reisler Emil, Houk K.N., Quantitative evaluation of the lengths of homobifunctional protein cross-linking reagents used as molecular rulers, 10.1110/ps.51201
  32. Protein Sci., 4, 521 (1995)
  33. Moriki Takanori, Maruyama Hiroko, Maruyama Ichi N, Activation of preformed EGF receptor dimers by ligand-induced rotation of the transmembrane domain11Edited by B. Holland, 10.1006/jmbi.2001.4923
  34. Ruan Weiming, Becker Verena, Klingmüller Ursula, Langosch Dieter, The Interface between Self-assembling Erythropoietin Receptor Transmembrane Segments Corresponds to a Membrane-spanning Leucine Zipper, 10.1074/jbc.m309311200
  35. Witthuhn Bruce A., Quelle Frederick W., Silvennoinen Olli, Yi Taolin, Tang Bo, Miura Osamu, Ihle James N., JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin, 10.1016/0092-8674(93)90414-l
  36. Aurora Rajeev, Rosee George D., Helix capping, 10.1002/pro.5560070103
  37. Saitô Hazime, Conformation-dependent13C chemical shifts: A new means of conformational characterization as obtained by high-resolution solid-state13C NMR, 10.1002/mrc.1260241002
  38. Tjandra Nico, Bax Ad, Large Variations in13CαChemical Shift Anisotropy in Proteins Correlate with Secondary Structure, 10.1021/ja9721374
  39. Gurezka Rolf, Laage Rico, Brosig Bettina, Langosch Dieter, A Heptad Motif of Leucine Residues Found in Membrane Proteins Can Drive Self-assembly of Artificial Transmembrane Segments, 10.1074/jbc.274.14.9265
  40. Walters Kylie J., Dayie Kwaku T., Reece Richard J., Ptashne Mark, Wagner Gerhard, Structure and mobility of the PUT3 dimer, 10.1038/nsb0997-744
  41. Swaminathan Kunchithapadam, Flynn Paul, Reece Richard J., Marmorstein Ronen, Crystal structure of a PUT3–DNA complex reveals a novel mechanism for DMA recognition by a protein containing a Zn2Cys6 binuclear cluster, 10.1038/nsb0997-751
  42. Minor Daniel L., Kim Peter S., Context is a major determinant of β-sheet propensity, 10.1038/371264a0
  43. Elliott Steve, Lorenzini Tony, Yanagihara Donna, Chang David, Elliott Gary, Activation of the Erythropoietin (EPO) Receptor by Bivalent Anti-EPO Receptor Antibodies, 10.1074/jbc.271.40.24691
  44. Wrighton N. C., Farrell F. X., Chang R., Kashyap A. K., Barbone F. P., Mulcahy L. S., Johnson D. L., Barrett R. W., Jolliffe L. K., Dower W. J., Small Peptides as Potent Mimetics of the Protein Hormone Erythropoietin, 10.1126/science.273.5274.458
  45. Li Jing-Po, D'Andrea Alan D., Lodish Harvey F., Baltimore David, Activation of cell growth by binding of Friend spleen focus-forming virus gp55 glycoprotein to the erythropoietin receptor, 10.1038/343762a0
  46. Darnell Jr. J. E., STATs and Gene Regulation, 10.1126/science.277.5332.1630
  47. Hoatlin M. E., Kozak S. L., Lilly F., Chakraborti A., Kozak C. A., Kabat D., Activation of erythropoietin receptors by Friend viral gp55 and by erythropoietin and down-modulation by the murine Fv-2r resistance gene., 10.1073/pnas.87.24.9985
  48. J. Virol., 64, 1057 (1990)
  49. Syed Rashid S., Reid Scott W., Li Cuiwei, Cheetham Janet C., Aoki Kenneth H., Liu Beishan, Zhan Hangjun, Osslund Timothy D., Chirino Arthur J., Zhang Jiandong, Finer-Moore Janet, Elliott Steven, Sitney Karen, Katz Bradley A., Matthews David J., Wendoloski John J., Egrie Joan, Stroud Robert M., 10.1038/26773
  50. Livnah O., Stura E. A., Johnson D. L., Middleton S. A., Mulcahy L. S., Wrighton N. C., Dower W. J., Jolliffe L. K., Wilson I. A., Functional Mimicry of a Protein Hormone by a Peptide Agonist: The EPO Receptor Complex at 2.8 A, 10.1126/science.273.5274.464
  51. Livnah Oded, Johnson Dana L., Stura Enrico A., Farrell Francis X., Barbone Francis P., You Yun, Liu Kathleen D., Goldsmith Mark A., He Wen, Krause Christopher D., Pestka Sidney, Jolliffe Linda K., Wilson Ian A., An antagonist peptide–EPO receptor complex suggests that receptor dimerization is not sufficient for activation, 10.1038/2965
  52. Livnah O., Stura E. A., Middleton S. A., Johnson D. L., Jolliffe L. K., Wilson I. A., Crystallographic Evidence for Preformed Dimers of Erythropoietin Receptor Before Ligand Activation, 10.1126/science.283.5404.987
Bibliographic reference Kubatzky, KF ; Liu, W. ; Goldgraben, K ; Simmerling, C ; Smith, SO ; et. al. Structural requirements of the extracellular to transmembrane domain junction for erythropoietin receptor function. In: Journal of Biological Chemistry, Vol. 280, no. 15, p. 14844-14854 (2005)
Permanent URL http://hdl.handle.net/2078.1/39390