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2l6w

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2l6w, 20 NMR models ()
Gene: PDGFRB (HUMAN)
Activity: Receptor protein-tyrosine kinase, with EC number 2.7.10.1
Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml


Contents

PDGFR beta-TM

Publication Abstract from PubMed

The platelet-derived growth factor receptor beta 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 degrees to 30 degrees 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 beta 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.

Hydrophobic matching controls the tilt and stability of the dimeric platelet-derived growth factor receptor (PDGFR) beta transmembrane segment., Muhle-Goll C, Hoffmann S, Afonin S, Grage SL, Polyansky AA, Windisch D, Zeitler M, Burck J, Ulrich AS, J Biol Chem. 2012 Jul 27;287(31):26178-86. doi: 10.1074/jbc.M111.325555. Epub, 2012 May 22. PMID:22619173

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Disease

[PGFRB_HUMAN] Note=A chromosomal aberration involving PDGFRB is found in a form of chronic myelomonocytic leukemia (CMML). Translocation t(5;12)(q33;p13) with EVT6/TEL. It is characterized by abnormal clonal myeloid proliferation and by progression to acute myelogenous leukemia (AML). Note=A chromosomal aberration involving PDGFRB may be a cause of acute myelogenous leukemia. Translocation t(5;14)(q33;q32) with TRIP11. The fusion protein may be involved in clonal evolution of leukemia and eosinophilia. Note=A chromosomal aberration involving PDGFRB may be a cause of juvenile myelomonocytic leukemia. Translocation t(5;17)(q33;p11.2) with SPECC1. Defects in PDGFRB are a cause of myeloproliferative disorder chronic with eosinophilia (MPE) [MIM:131440]. A hematologic disorder characterized by malignant eosinophils proliferation. Note=A chromosomal aberration involving PDGFRB is found in many instances of myeloproliferative disorder chronic with eosinophilia. Translocation t(5;12) with ETV6 on chromosome 12 creating an PDGFRB-ETV6 fusion protein. Translocation t(5;15)(q33;q22) with TP53BP1 creating a PDGFRB-TP53BP1 fusion protein. Note=A chromosomal aberration involving PDGFRB may be the cause of a myeloproliferative disorder (MBD) associated with eosinophilia. Translocation t(1;5)(q23;q33) that forms a PDE4DIP-PDGFRB fusion protein. Note=A chromosomal aberration involving PGFRB is found in a patient with T-lymphoblastic lymphoma (T-ALL) and an associated myeloproliferative neoplasm (MPN) with eosinophilia. Translocation t(5;6)(q33-34;q23) with CEP85L. The translocation fuses the 5'-end of CEP85L (isoform 4) to the 3'-end of PDGFRB.

Function

[PGFRB_HUMAN] Tyrosine-protein kinase that acts as cell-surface receptor for homodimeric PDGFB and PDGFD and for heterodimers formed by PDGFA and PDGFB, and plays an essential role in the regulation of embryonic development, cell proliferation, survival, differentiation, chemotaxis and migration. Plays an essential role in blood vessel development by promoting proliferation, migration and recruitment of pericytes and smooth muscle cells to endothelial cells. Plays a role in the migration of vascular smooth muscle cells and the formation of neointima at vascular injury sites. Required for normal development of the cardiovascular system. Required for normal recruitment of pericytes (mesangial cells) in the kidney glomerulus, and for normal formation of a branched network of capillaries in kidney glomeruli. Promotes rearrangement of the actin cytoskeleton and the formation of membrane ruffles. Binding of its cognate ligands - homodimeric PDGFB, heterodimers formed by PDGFA and PDGFB or homodimeric PDGFD -leads to the activation of several signaling cascades; the response depends on the nature of the bound ligand and is modulated by the formation of heterodimers between PDGFRA and PDGFRB. Phosphorylates PLCG1, PIK3R1, PTPN11, RASA1/GAP, CBL, SHC1 and NCK1. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate, mobilization of cytosolic Ca(2+) and the activation of protein kinase C. Phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leads to the activation of the AKT1 signaling pathway. Phosphorylation of SHC1, or of the C-terminus of PTPN11, creates a binding site for GRB2, resulting in the activation of HRAS, RAF1 and down-stream MAP kinases, including MAPK1/ERK2 and/or MAPK3/ERK1. Promotes phosphorylation and activation of SRC family kinases. Promotes phosphorylation of PDCD6IP/ALIX and STAM. Receptor signaling is down-regulated by protein phosphatases that dephosphorylate the receptor and its down-stream effectors, and by rapid internalization of the activated receptor.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19]

About this Structure

2l6w is a 2 chain structure with sequence from Human. Full experimental information is available from OCA.

Reference

  • Muhle-Goll C, Hoffmann S, Afonin S, Grage SL, Polyansky AA, Windisch D, Zeitler M, Burck J, Ulrich AS. Hydrophobic matching controls the tilt and stability of the dimeric platelet-derived growth factor receptor (PDGFR) beta transmembrane segment. J Biol Chem. 2012 Jul 27;287(31):26178-86. doi: 10.1074/jbc.M111.325555. Epub, 2012 May 22. PMID:22619173 doi:http://dx.doi.org/10.1074/jbc.M111.325555
  1. Gronwald RG, Grant FJ, Haldeman BA, Hart CE, O'Hara PJ, Hagen FS, Ross R, Bowen-Pope DF, Murray MJ. Cloning and expression of a cDNA coding for the human platelet-derived growth factor receptor: evidence for more than one receptor class. Proc Natl Acad Sci U S A. 1988 May;85(10):3435-9. PMID:2835772
  2. Claesson-Welsh L, Eriksson A, Moren A, Severinsson L, Ek B, Ostman A, Betsholtz C, Heldin CH. cDNA cloning and expression of a human platelet-derived growth factor (PDGF) receptor specific for B-chain-containing PDGF molecules. Mol Cell Biol. 1988 Aug;8(8):3476-86. PMID:2850496
  3. Matsui T, Pierce JH, Fleming TP, Greenberger JS, LaRochelle WJ, Ruggiero M, Aaronson SA. Independent expression of human alpha or beta platelet-derived growth factor receptor cDNAs in a naive hematopoietic cell leads to functional coupling with mitogenic and chemotactic signaling pathways. Proc Natl Acad Sci U S A. 1989 Nov;86(21):8314-8. PMID:2554309
  4. Kazlauskas A, Durden DL, Cooper JA. Functions of the major tyrosine phosphorylation site of the PDGF receptor beta subunit. Cell Regul. 1991 Jun;2(6):413-25. PMID:1653029
  5. Kelly JD, Haldeman BA, Grant FJ, Murray MJ, Seifert RA, Bowen-Pope DF, Cooper JA, Kazlauskas A. Platelet-derived growth factor (PDGF) stimulates PDGF receptor subunit dimerization and intersubunit trans-phosphorylation. J Biol Chem. 1991 May 15;266(14):8987-92. PMID:1709159
  6. Sorkin A, Westermark B, Heldin CH, Claesson-Welsh L. Effect of receptor kinase inactivation on the rate of internalization and degradation of PDGF and the PDGF beta-receptor. J Cell Biol. 1991 Feb;112(3):469-78. PMID:1846866
  7. Kashishian A, Kazlauskas A, Cooper JA. Phosphorylation sites in the PDGF receptor with different specificities for binding GAP and PI3 kinase in vivo. EMBO J. 1992 Apr;11(4):1373-82. PMID:1314164
  8. Ronnstrand L, Mori S, Arridsson AK, Eriksson A, Wernstedt C, Hellman U, Claesson-Welsh L, Heldin CH. Identification of two C-terminal autophosphorylation sites in the PDGF beta-receptor: involvement in the interaction with phospholipase C-gamma. EMBO J. 1992 Nov;11(11):3911-9. PMID:1396585
  9. Mori S, Ronnstrand L, Yokote K, Engstrom A, Courtneidge SA, Claesson-Welsh L, Heldin CH. Identification of two juxtamembrane autophosphorylation sites in the PDGF beta-receptor; involvement in the interaction with Src family tyrosine kinases. EMBO J. 1993 Jun;12(6):2257-64. PMID:7685273
  10. Lechleider RJ, Sugimoto S, Bennett AM, Kashishian AS, Cooper JA, Shoelson SE, Walsh CT, Neel BG. Activation of the SH2-containing phosphotyrosine phosphatase SH-PTP2 by its binding site, phosphotyrosine 1009, on the human platelet-derived growth factor receptor. J Biol Chem. 1993 Oct 15;268(29):21478-81. PMID:7691811
  11. Nishimura R, Li W, Kashishian A, Mondino A, Zhou M, Cooper J, Schlessinger J. Two signaling molecules share a phosphotyrosine-containing binding site in the platelet-derived growth factor receptor. Mol Cell Biol. 1993 Nov;13(11):6889-96. PMID:7692233
  12. Gilbertson DG, Duff ME, West JW, Kelly JD, Sheppard PO, Hofstrand PD, Gao Z, Shoemaker K, Bukowski TR, Moore M, Feldhaus AL, Humes JM, Palmer TE, Hart CE. Platelet-derived growth factor C (PDGF-C), a novel growth factor that binds to PDGF alpha and beta receptor. J Biol Chem. 2001 Jul 20;276(29):27406-14. Epub 2001 Apr 10. PMID:11297552 doi:10.1074/jbc.M101056200
  13. Bergsten E, Uutela M, Li X, Pietras K, Ostman A, Heldin CH, Alitalo K, Eriksson U. PDGF-D is a specific, protease-activated ligand for the PDGF beta-receptor. Nat Cell Biol. 2001 May;3(5):512-6. PMID:11331881 doi:10.1038/35074588
  14. Ustach CV, Huang W, Conley-LaComb MK, Lin CY, Che M, Abrams J, Kim HR. A novel signaling axis of matriptase/PDGF-D/ss-PDGFR in human prostate cancer. Cancer Res. 2010 Dec 1;70(23):9631-40. doi: 10.1158/0008-5472.CAN-10-0511. Epub, 2010 Nov 23. PMID:21098708 doi:10.1158/0008-5472.CAN-10-0511
  15. Wardega P, Heldin CH, Lennartsson J. Mutation of tyrosine residue 857 in the PDGF beta-receptor affects cell proliferation but not migration. Cell Signal. 2010 Sep;22(9):1363-8. doi: 10.1016/j.cellsig.2010.05.004. Epub 2010, May 18. PMID:20494825 doi:10.1016/j.cellsig.2010.05.004
  16. Mendelson K, Swendeman S, Saftig P, Blobel CP. Stimulation of platelet-derived growth factor receptor beta (PDGFRbeta) activates ADAM17 and promotes metalloproteinase-dependent cross-talk between the PDGFRbeta and epidermal growth factor receptor (EGFR) signaling pathways. J Biol Chem. 2010 Aug 6;285(32):25024-32. doi: 10.1074/jbc.M110.102566. Epub 2010, Jun 7. PMID:20529858 doi:10.1074/jbc.M110.102566
  17. Kim HJ, Cha BY, Choi B, Lim JS, Woo JT, Kim JS. Glyceollins inhibit platelet-derived growth factor-mediated human arterial smooth muscle cell proliferation and migration. Br J Nutr. 2012 Jan;107(1):24-35. doi: 10.1017/S0007114511002571. Epub 2011 Jun, 29. PMID:21733313 doi:10.1017/S0007114511002571
  18. Yokote K, Mori S, Hansen K, McGlade J, Pawson T, Heldin CH, Claesson-Welsh L. Direct interaction between Shc and the platelet-derived growth factor beta-receptor. J Biol Chem. 1994 May 27;269(21):15337-43. PMID:8195171
  19. Caglayan E, Vantler M, Leppanen O, Gerhardt F, Mustafov L, Ten Freyhaus H, Kappert K, Odenthal M, Zimmermann WH, Tallquist MD, Rosenkranz S. Disruption of platelet-derived growth factor-dependent phosphatidylinositol 3-kinase and phospholipase Cgamma 1 activity abolishes vascular smooth muscle cell proliferation and migration and attenuates neointima formation in vivo. J Am Coll Cardiol. 2011 Jun 21;57(25):2527-38. doi: 10.1016/j.jacc.2011.02.037. PMID:21679854 doi:10.1016/j.jacc.2011.02.037

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