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Contents

NGF IN COMPLEX WITH DOMAIN 5 OF THE TRKA RECEPTOR

Publication Abstract from PubMed

Nerve growth factor (NGF) is involved in a variety of processes involving signalling, such as cell differentiation and survival, growth cessation and apoptosis of neurons. These events are mediated by NGF as a result of binding to its two cell-surface receptors, TrkA and p75. TrkA is a receptor with tyrosine kinase activity that forms a high-affinity binding site for NGF. Of the five domains comprising its extracellular portion, the immunoglobulin-like domain proximal to the membrane (TrkA-d5 domain) is necessary and sufficient for NGF binding. Here we present the crystal structure of human NGF in complex with human TrkA-d5 at 2.2 A resolution. The ligand-receptor interface consists of two patches of similar size. One patch involves the central beta-sheet that forms the core of the homodimeric NGF molecule and the loops at the carboxy-terminal pole of TrkA-d5. The second patch comprises the amino-terminal residues of NGF, which adopt a helical conformation upon complex formation, packing against the 'ABED' sheet of TrkA-d5. The structure is consistent with results from mutagenesis experiments for all neurotrophins, and indicates that the first patch may constitute a conserved binding motif for all family members, whereas the second patch is specific for the interaction between NGF and TrkA.

Crystal structure of nerve growth factor in complex with the ligand-binding domain of the TrkA receptor., Wiesmann C, Ultsch MH, Bass SH, de Vos AM, Nature. 1999 Sep 9;401(6749):184-8. PMID:10490030

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

Disease

[NGF_HUMAN] Defects in NGF are the cause of hereditary sensory and autonomic neuropathy type 5 (HSAN5) [MIM:608654]. The hereditary sensory and autonomic neuropathies are a genetically and clinically heterogeneous group of disorders characterized by degeneration of dorsal root and autonomic ganglion cells, and by sensory and/or autonomic abnormalities. HSAN5 patients manifest loss of pain perception and impaired temperature sensitivity, ulcers, and in some cases self-mutilation. The autonomic involvement is variable.[1][2][3] [NTRK1_HUMAN] Defects in NTRK1 are a cause of congenital insensitivity to pain with anhidrosis (CIPA) [MIM:256800]. CIPA is characterized by a congenital insensitivity to pain, anhidrosis (absence of sweating), absence of reaction to noxious stimuli, self-mutilating behavior, and mental retardation. This rare autosomal recessive disorder is also known as congenital sensory neuropathy with anhidrosis or hereditary sensory and autonomic neuropathy type IV or familial dysautonomia type II.[4][5][6][7][8][9][10][11][12][13] Defects in NTRK1 are a cause of thyroid papillary carcinoma (TPC) [MIM:188550]. TPC is a common tumor of the thyroid that typically arises as an irregular, solid or cystic mass from otherwise normal thyroid tissue. Papillary carcinomas are malignant neoplasm characterized by the formation of numerous, irregular, finger-like projections of fibrous stroma that is covered with a surface layer of neoplastic epithelial cells. Note=Chromosomal aberrations involving NTRK1 are found in thyroid papillary carcinomas. Translocation t(1;3)(q21;q11) with TFG generates the TRKT3 (TRK-T3) transcript by fusing TFG to the 3'-end of NTRK1; a rearrangement with TPM3 generates the TRK transcript by fusing TPM3 to the 3'-end of NTRK1; an intrachromosomal rearrangement that links the protein kinase domain of NTRK1 to the 5'-end of the TPR gene forms the fusion protein TRK-T1. TRK-T1 is a 55 kDa protein reacting with antibodies against the C-terminus of the NTRK1 protein.

Function

[NGF_HUMAN] Nerve growth factor is important for the development and maintenance of the sympathetic and sensory nervous systems. Extracellular ligand for the NTRK1 and NGFR receptors, activates cellular signaling cascades through those receptor tyrosine kinase to regulate neuronal proliferation, differentiation and survival. [NTRK1_HUMAN] Receptor tyrosine kinase involved in the development and the maturation of the central and peripheral nervous systems through regulation of proliferation, differentiation and survival of sympathetic and nervous neurons. High affinity receptor for NGF which is its primary ligand, it can also bind and be activated by NTF3/neurotrophin-3. However, NTF3 only supports axonal extension through NTRK1 but has no effect on neuron survival. Upon dimeric NGF ligand-binding, undergoes homodimerization, autophosphorylation and activation. Recruits, phosphorylates and/or activates several downstream effectors including SHC1, FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlapping signaling cascades driving cell survival and differentiation. Through SHC1 and FRS2 activates a GRB2-Ras-MAPK cascade that regulates cell differentiation and survival. Through PLCG1 controls NF-Kappa-B activation and the transcription of genes involved in cell survival. Through SHC1 and SH2B1 controls a Ras-PI3 kinase-AKT1 signaling cascade that is also regulating survival. In absence of ligand and activation, may promote cell death, making the survival of neurons dependent on trophic factors.[14][15][16][17][18][19] Isoform TrkA-III is resistant to NGF, constitutively activates AKT1 and NF-kappa-B and is unable to activate the Ras-MAPK signaling cascade. Antagonizes the anti-proliferative NGF-NTRK1 signaling that promotes neuronal precursors differentiation. Isoform TrkA-III promotes angiogenesis and has oncogenic activity when overexpressed.[20][21][22][23][24][25]

About this Structure

1www is a 4 chain structure with sequence from Homo sapiens. The August 2005 RCSB PDB Molecule of the Month feature on Neurotrophins by David S. Goodsell is 10.2210/rcsb_pdb/mom_2005_8. Full crystallographic information is available from OCA.

Reference

  • Wiesmann C, Ultsch MH, Bass SH, de Vos AM. Crystal structure of nerve growth factor in complex with the ligand-binding domain of the TrkA receptor. Nature. 1999 Sep 9;401(6749):184-8. PMID:10490030 doi:10.1038/43705
  1. Einarsdottir E, Carlsson A, Minde J, Toolanen G, Svensson O, Solders G, Holmgren G, Holmberg D, Holmberg M. A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception. Hum Mol Genet. 2004 Apr 15;13(8):799-805. Epub 2004 Feb 19. PMID:14976160 doi:10.1093/hmg/ddh096
  2. Carvalho OP, Thornton GK, Hertecant J, Houlden H, Nicholas AK, Cox JJ, Rielly M, Al-Gazali L, Woods CG. A novel NGF mutation clarifies the molecular mechanism and extends the phenotypic spectrum of the HSAN5 neuropathy. J Med Genet. 2011 Feb;48(2):131-5. doi: 10.1136/jmg.2010.081455. Epub 2010 Oct, 26. PMID:20978020 doi:10.1136/jmg.2010.081455
  3. Davidson G, Murphy S, Polke J, Laura M, Salih M, Muntoni F, Blake J, Brandner S, Davies N, Horvath R, Price S, Donaghy M, Roberts M, Foulds N, Ramdharry G, Soler D, Lunn M, Manji H, Davis M, Houlden H, Reilly M. Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort. J Neurol. 2012 Aug;259(8):1673-85. PMID:22302274 doi:10.1007/s00415-011-6397-y
  4. Indo Y, Tsuruta M, Hayashida Y, Karim MA, Ohta K, Kawano T, Mitsubuchi H, Tonoki H, Awaya Y, Matsuda I. Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis. Nat Genet. 1996 Aug;13(4):485-8. PMID:8696348 doi:10.1038/ng0896-485
  5. Greco A, Villa R, Tubino B, Romano L, Penso D, Pierotti MA. A novel NTRK1 mutation associated with congenital insensitivity to pain with anhidrosis. Am J Hum Genet. 1999 Apr;64(4):1207-10. PMID:10090906
  6. Mardy S, Miura Y, Endo F, Matsuda I, Sztriha L, Frossard P, Moosa A, Ismail EA, Macaya A, Andria G, Toscano E, Gibson W, Graham GE, Indo Y. Congenital insensitivity to pain with anhidrosis: novel mutations in the TRKA (NTRK1) gene encoding a high-affinity receptor for nerve growth factor. Am J Hum Genet. 1999 Jun;64(6):1570-9. PMID:10330344 doi:10.1086/302422
  7. Yotsumoto S, Setoyama M, Hozumi H, Mizoguchi S, Fukumaru S, Kobayashi K, Saheki T, Kanzaki T. A novel point mutation affecting the tyrosine kinase domain of the TRKA gene in a family with congenital insensitivity to pain with anhidrosis. J Invest Dermatol. 1999 May;112(5):810-4. PMID:10233776 doi:10.1046/j.1523-1747.1999.00569.x
  8. Shatzky S, Moses S, Levy J, Pinsk V, Hershkovitz E, Herzog L, Shorer Z, Luder A, Parvari R. Congenital insensitivity to pain with anhidrosis (CIPA) in Israeli-Bedouins: genetic heterogeneity, novel mutations in the TRKA/NGF receptor gene, clinical findings, and results of nerve conduction studies. Am J Med Genet. 2000 Jun 19;92(5):353-60. PMID:10861667
  9. Miura Y, Mardy S, Awaya Y, Nihei K, Endo F, Matsuda I, Indo Y. Mutation and polymorphism analysis of the TRKA (NTRK1) gene encoding a high-affinity receptor for nerve growth factor in congenital insensitivity to pain with anhidrosis (CIPA) families. Hum Genet. 2000 Jan;106(1):116-24. PMID:10982191
  10. Greco A, Villa R, Fusetti L, Orlandi R, Pierotti MA. The Gly571Arg mutation, associated with the autonomic and sensory disorder congenital insensitivity to pain with anhidrosis, causes the inactivation of the NTRK1/nerve growth factor receptor. J Cell Physiol. 2000 Jan;182(1):127-33. PMID:10567924 doi:<127::AID-JCP14>3.0.CO;2-0 10.1002/(SICI)1097-4652(200001)182:1<127::AID-JCP14>3.0.CO;2-0
  11. Houlden H, King RH, Hashemi-Nejad A, Wood NW, Mathias CJ, Reilly M, Thomas PK. A novel TRK A (NTRK1) mutation associated with hereditary sensory and autonomic neuropathy type V. Ann Neurol. 2001 Apr;49(4):521-5. PMID:11310631
  12. Mardy S, Miura Y, Endo F, Matsuda I, Indo Y. Congenital insensitivity to pain with anhidrosis (CIPA): effect of TRKA (NTRK1) missense mutations on autophosphorylation of the receptor tyrosine kinase for nerve growth factor. Hum Mol Genet. 2001 Feb 1;10(3):179-88. PMID:11159935
  13. Davidson G, Murphy S, Polke J, Laura M, Salih M, Muntoni F, Blake J, Brandner S, Davies N, Horvath R, Price S, Donaghy M, Roberts M, Foulds N, Ramdharry G, Soler D, Lunn M, Manji H, Davis M, Houlden H, Reilly M. Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort. J Neurol. 2012 Aug;259(8):1673-85. PMID:22302274 doi:10.1007/s00415-011-6397-y
  14. Hempstead BL, Martin-Zanca D, Kaplan DR, Parada LF, Chao MV. High-affinity NGF binding requires coexpression of the trk proto-oncogene and the low-affinity NGF receptor. Nature. 1991 Apr 25;350(6320):678-83. PMID:1850821 doi:http://dx.doi.org/10.1038/350678a0
  15. Klein R, Jing SQ, Nanduri V, O'Rourke E, Barbacid M. The trk proto-oncogene encodes a receptor for nerve growth factor. Cell. 1991 Apr 5;65(1):189-97. PMID:1849459
  16. Barker PA, Lomen-Hoerth C, Gensch EM, Meakin SO, Glass DJ, Shooter EM. Tissue-specific alternative splicing generates two isoforms of the trkA receptor. J Biol Chem. 1993 Jul 15;268(20):15150-7. PMID:8325889
  17. Stephens RM, Loeb DM, Copeland TD, Pawson T, Greene LA, Kaplan DR. Trk receptors use redundant signal transduction pathways involving SHC and PLC-gamma 1 to mediate NGF responses. Neuron. 1994 Mar;12(3):691-705. PMID:8155326
  18. Wooten MW, Seibenhener ML, Mamidipudi V, Diaz-Meco MT, Barker PA, Moscat J. The atypical protein kinase C-interacting protein p62 is a scaffold for NF-kappaB activation by nerve growth factor. J Biol Chem. 2001 Mar 16;276(11):7709-12. Epub 2001 Jan 22. PMID:11244088 doi:10.1074/jbc.C000869200
  19. Tacconelli A, Farina AR, Cappabianca L, Desantis G, Tessitore A, Vetuschi A, Sferra R, Rucci N, Argenti B, Screpanti I, Gulino A, Mackay AR. TrkA alternative splicing: a regulated tumor-promoting switch in human neuroblastoma. Cancer Cell. 2004 Oct;6(4):347-60. PMID:15488758 doi:10.1016/j.ccr.2004.09.011
  20. Hempstead BL, Martin-Zanca D, Kaplan DR, Parada LF, Chao MV. High-affinity NGF binding requires coexpression of the trk proto-oncogene and the low-affinity NGF receptor. Nature. 1991 Apr 25;350(6320):678-83. PMID:1850821 doi:http://dx.doi.org/10.1038/350678a0
  21. Klein R, Jing SQ, Nanduri V, O'Rourke E, Barbacid M. The trk proto-oncogene encodes a receptor for nerve growth factor. Cell. 1991 Apr 5;65(1):189-97. PMID:1849459
  22. Barker PA, Lomen-Hoerth C, Gensch EM, Meakin SO, Glass DJ, Shooter EM. Tissue-specific alternative splicing generates two isoforms of the trkA receptor. J Biol Chem. 1993 Jul 15;268(20):15150-7. PMID:8325889
  23. Stephens RM, Loeb DM, Copeland TD, Pawson T, Greene LA, Kaplan DR. Trk receptors use redundant signal transduction pathways involving SHC and PLC-gamma 1 to mediate NGF responses. Neuron. 1994 Mar;12(3):691-705. PMID:8155326
  24. Wooten MW, Seibenhener ML, Mamidipudi V, Diaz-Meco MT, Barker PA, Moscat J. The atypical protein kinase C-interacting protein p62 is a scaffold for NF-kappaB activation by nerve growth factor. J Biol Chem. 2001 Mar 16;276(11):7709-12. Epub 2001 Jan 22. PMID:11244088 doi:10.1074/jbc.C000869200
  25. Tacconelli A, Farina AR, Cappabianca L, Desantis G, Tessitore A, Vetuschi A, Sferra R, Rucci N, Argenti B, Screpanti I, Gulino A, Mackay AR. TrkA alternative splicing: a regulated tumor-promoting switch in human neuroblastoma. Cancer Cell. 2004 Oct;6(4):347-60. PMID:15488758 doi:10.1016/j.ccr.2004.09.011

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