1he7

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1he7, resolution 2.00Å ()
Ligands:
Activity: Transferase, with EC number and 2.7.10.2 2.7.10.1 and 2.7.10.2
Related: 1wwa, 1www
Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml


Contents

HUMAN NERVE GROWTH FACTOR RECEPTOR TRKA

Publication Abstract from PubMed

Nerve growth factor (NGF) is involved in the development and maintenance of the nervous system and has been implicated as a possible therapeutic target molecule in a number of neurodegenerative diseases, especially Alzheimer's disease. NGF binds with high affinity to the extracellular region of a tyrosine kinase receptor, TrkA, which comprises three leucine-rich motifs (LRMs), flanked by two cysteine-rich clusters, followed by two immunoglobulin-like (Ig-like) domains. We have expressed the second Ig-like domain as a recombinant protein in E. coli and demonstrate that NGF binds to this domain with similar affinity to the native receptor. This domain (TrkAIg(2)) has the ability to sequester NGF in vitro, preventing NGF-induced neurite outgrowth, and in vivo, inhibiting NGF-induced plasma extravasation. We also present the three-dimensional structure of the TrkAIg(2) domain in a new crystal form, refined to 2.0 A resolution.

Identification and structure of the nerve growth factor binding site on TrkA., Robertson AG, Banfield MJ, Allen SJ, Dando JA, Mason GG, Tyler SJ, Bennett GS, Brain SD, Clarke AR, Naylor RL, Wilcock GK, Brady RL, Dawbarn D, Biochem Biophys Res Commun. 2001 Mar 23;282(1):131-41. PMID:11263982

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

Disease

[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.[1][2][3][4][5][6][7][8][9][10] 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

[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.[11][12][13][14][15][16] 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.[17][18][19][20][21][22]

About this Structure

1he7 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

  • Robertson AG, Banfield MJ, Allen SJ, Dando JA, Mason GG, Tyler SJ, Bennett GS, Brain SD, Clarke AR, Naylor RL, Wilcock GK, Brady RL, Dawbarn D. Identification and structure of the nerve growth factor binding site on TrkA. Biochem Biophys Res Commun. 2001 Mar 23;282(1):131-41. PMID:11263982 doi:10.1006/bbrc.2001.4462
  • Ultsch MH, Wiesmann C, Simmons LC, Henrich J, Yang M, Reilly D, Bass SH, de Vos AM. Crystal structures of the neurotrophin-binding domain of TrkA, TrkB and TrkC. J Mol Biol. 1999 Jul 2;290(1):149-59. PMID:10388563 doi:10.1006/jmbi.1999.2816
  • 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. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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
  11. 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
  12. 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
  13. 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
  14. 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
  15. 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
  16. 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
  17. 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
  18. 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
  19. 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
  20. 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
  21. 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
  22. 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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