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. 1999 Nov;8(11):2223–2233. doi: 10.1110/ps.8.11.2223

The interaction of neurotrophins with the p75NTR common neurotrophin receptor: a comprehensive molecular modeling study.

I L Shamovsky 1, G M Ross 1, R J Riopelle 1, D F Weaver 1
PMCID: PMC2144181  PMID: 10595525

Abstract

Neurotrophins are a family of proteins with pleiotropic effects mediated by two distinct receptor types, namely the Trk family, and the common neurotrophin receptor p75NTR. Binding of four mammalian neurotrophins, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4/5 (NT-4/5), to p75NTR is studied by molecular modeling based on X-ray structures of the neurotrophins and the extracellular domain of p55TNFR, a homologue of p75NTR. The model of neurotrophin/receptor interactions suggests that the receptor binding domains of neurotrophins (loops I and IV) are geometrically and electrostatically complementary to a putative binding site of p75NTR, formed by the second and part of the third cysteine-rich domains. Geometric match of neurotrophin/receptor binding domains in the complexes, as characterized by shape complementarity statistic Sc, is comparable to known protein/protein complexes. All charged residues within the loops I and IV of the neurotrophins, previously determined as being critical for p75NTR binding, directly participate in receptor binding in the framework of the model. Principal residues of the binding site of p75NTR include Asp47, Lys56, Asp75, Asp76, Asp88, and Glu89. The additional involvement of Arg80 and Glu53 is specific for NGF and BDNF, respectively, and Glu73 participates in binding with NT-3 and NT-4/5. Neurotrophins are likely to induce similar, but not identical, conformational changes within the p75NTR binding site.

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Selected References

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  1. Anton E. S., Weskamp G., Reichardt L. F., Matthew W. D. Nerve growth factor and its low-affinity receptor promote Schwann cell migration. Proc Natl Acad Sci U S A. 1994 Mar 29;91(7):2795–2799. doi: 10.1073/pnas.91.7.2795. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Baldwin A. N., Shooter E. M. Disulfide mutants of the binding domain of the rat low affinity nerve growth factor receptor (p75NGFR). J Biol Chem. 1994 Apr 15;269(15):11456–11461. [PubMed] [Google Scholar]
  3. Baldwin A. N., Shooter E. M. Zone mapping of the binding domain of the rat low affinity nerve growth factor receptor by the introduction of novel N-glycosylation sites. J Biol Chem. 1995 Mar 3;270(9):4594–4602. doi: 10.1074/jbc.270.9.4594. [DOI] [PubMed] [Google Scholar]
  4. Banner D. W., D'Arcy A., Janes W., Gentz R., Schoenfeld H. J., Broger C., Loetscher H., Lesslauer W. Crystal structure of the soluble human 55 kd TNF receptor-human TNF beta complex: implications for TNF receptor activation. Cell. 1993 May 7;73(3):431–445. doi: 10.1016/0092-8674(93)90132-a. [DOI] [PubMed] [Google Scholar]
  5. Barbacid M. Nerve growth factor: a tale of two receptors. Oncogene. 1993 Aug;8(8):2033–2042. [PubMed] [Google Scholar]
  6. Barbacid M. The Trk family of neurotrophin receptors. J Neurobiol. 1994 Nov;25(11):1386–1403. doi: 10.1002/neu.480251107. [DOI] [PubMed] [Google Scholar]
  7. Barde Y. A. Trophic factors and neuronal survival. Neuron. 1989 Jun;2(6):1525–1534. doi: 10.1016/0896-6273(89)90040-8. [DOI] [PubMed] [Google Scholar]
  8. Barker P. A., Shooter E. M. Disruption of NGF binding to the low affinity neurotrophin receptor p75LNTR reduces NGF binding to TrkA on PC12 cells. Neuron. 1994 Jul;13(1):203–215. doi: 10.1016/0896-6273(94)90470-7. [DOI] [PubMed] [Google Scholar]
  9. Barrett G. L., Bartlett P. F. The p75 nerve growth factor receptor mediates survival or death depending on the stage of sensory neuron development. Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6501–6505. doi: 10.1073/pnas.91.14.6501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Bax B., Blundell T. L., Murray-Rust J., McDonald N. Q. Structure of mouse 7S NGF: a complex of nerve growth factor with four binding proteins. Structure. 1997 Oct 15;5(10):1275–1285. doi: 10.1016/s0969-2126(97)00280-3. [DOI] [PubMed] [Google Scholar]
  11. Berkemeier L. R., Winslow J. W., Kaplan D. R., Nikolics K., Goeddel D. V., Rosenthal A. Neurotrophin-5: a novel neurotrophic factor that activates trk and trkB. Neuron. 1991 Nov;7(5):857–866. doi: 10.1016/0896-6273(91)90287-a. [DOI] [PubMed] [Google Scholar]
  12. Bothwell M. Functional interactions of neurotrophins and neurotrophin receptors. Annu Rev Neurosci. 1995;18:223–253. doi: 10.1146/annurev.ne.18.030195.001255. [DOI] [PubMed] [Google Scholar]
  13. Bradshaw R. A., Murray-Rust J., Ibáez C. F., McDonald N. Q., Lapatto R., Blundell T. L. Nerve growth factor: structure/function relationships. Protein Sci. 1994 Nov;3(11):1901–1913. doi: 10.1002/pro.5560031102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Butte M. J., Hwang P. K., Mobley W. C., Fletterick R. J. Crystal structure of neurotrophin-3 homodimer shows distinct regions are used to bind its receptors. Biochemistry. 1998 Dec 1;37(48):16846–16852. doi: 10.1021/bi981254o. [DOI] [PubMed] [Google Scholar]
  15. Carter B. D., Kaltschmidt C., Kaltschmidt B., Offenhäuser N., Böhm-Matthaei R., Baeuerle P. A., Barde Y. A. Selective activation of NF-kappa B by nerve growth factor through the neurotrophin receptor p75. Science. 1996 Apr 26;272(5261):542–545. doi: 10.1126/science.272.5261.542. [DOI] [PubMed] [Google Scholar]
  16. Casaccia-Bonnefil P., Carter B. D., Dobrowsky R. T., Chao M. V. Death of oligodendrocytes mediated by the interaction of nerve growth factor with its receptor p75. Nature. 1996 Oct 24;383(6602):716–719. doi: 10.1038/383716a0. [DOI] [PubMed] [Google Scholar]
  17. Chao M. V. Growth factor signaling: where is the specificity? Cell. 1992 Mar 20;68(6):995–997. doi: 10.1016/0092-8674(92)90068-n. [DOI] [PubMed] [Google Scholar]
  18. Chao M. V., Hempstead B. L. p75 and Trk: a two-receptor system. Trends Neurosci. 1995 Jul;18(7):321–326. [PubMed] [Google Scholar]
  19. Chao M. V. Neurotrophin receptors: a window into neuronal differentiation. Neuron. 1992 Oct;9(4):583–593. doi: 10.1016/0896-6273(92)90023-7. [DOI] [PubMed] [Google Scholar]
  20. Chao M. V. The p75 neurotrophin receptor. J Neurobiol. 1994 Nov;25(11):1373–1385. doi: 10.1002/neu.480251106. [DOI] [PubMed] [Google Scholar]
  21. Chapman B. S., Kuntz I. D. Modeled structure of the 75-kDa neurotrophin receptor. Protein Sci. 1995 Sep;4(9):1696–1707. doi: 10.1002/pro.5560040905. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Clackson T., Wells J. A. A hot spot of binding energy in a hormone-receptor interface. Science. 1995 Jan 20;267(5196):383–386. doi: 10.1126/science.7529940. [DOI] [PubMed] [Google Scholar]
  23. Davies A. M. The role of neurotrophins in the developing nervous system. J Neurobiol. 1994 Nov;25(11):1334–1348. doi: 10.1002/neu.480251103. [DOI] [PubMed] [Google Scholar]
  24. Dechant G., Barde Y. A. Signalling through the neurotrophin receptor p75NTR. Curr Opin Neurobiol. 1997 Jun;7(3):413–418. doi: 10.1016/s0959-4388(97)80071-2. [DOI] [PubMed] [Google Scholar]
  25. Dobrowsky R. T., Werner M. H., Castellino A. M., Chao M. V., Hannun Y. A. Activation of the sphingomyelin cycle through the low-affinity neurotrophin receptor. Science. 1994 Sep 9;265(5178):1596–1599. doi: 10.1126/science.8079174. [DOI] [PubMed] [Google Scholar]
  26. Drinkwater C. C., Suter U., Angst C., Shooter E. M. Mutation of tryptophan-21 in mouse nerve growth factor (NGF) affects binding to the fast NGF receptor but not induction of neurites on PC12 cells. Proc Biol Sci. 1991 Dec 23;246(1317):307–313. doi: 10.1098/rspb.1991.0159. [DOI] [PubMed] [Google Scholar]
  27. Farrah T., Smith C. A. Emerging cytokine family. Nature. 1992 Jul 2;358(6381):26–26. doi: 10.1038/358026b0. [DOI] [PubMed] [Google Scholar]
  28. Frade J. M., Barde Y. A. Microglia-derived nerve growth factor causes cell death in the developing retina. Neuron. 1998 Jan;20(1):35–41. doi: 10.1016/s0896-6273(00)80432-8. [DOI] [PubMed] [Google Scholar]
  29. Frade J. M., Rodríguez-Tébar A., Barde Y. A. Induction of cell death by endogenous nerve growth factor through its p75 receptor. Nature. 1996 Sep 12;383(6596):166–168. doi: 10.1038/383166a0. [DOI] [PubMed] [Google Scholar]
  30. Hallbök F., Ibáez C. F., Persson H. Evolutionary studies of the nerve growth factor family reveal a novel member abundantly expressed in Xenopus ovary. Neuron. 1991 May;6(5):845–858. doi: 10.1016/0896-6273(91)90180-8. [DOI] [PubMed] [Google Scholar]
  31. Heldin C. H., Ernlund A., Rorsman C., Rönnstrand L. Dimerization of B-type platelet-derived growth factor receptors occurs after ligand binding and is closely associated with receptor kinase activation. J Biol Chem. 1989 May 25;264(15):8905–8912. [PubMed] [Google Scholar]
  32. Herrmann J. L., Menter D. G., Hamada J., Marchetti D., Nakajima M., Nicolson G. L. Mediation of NGF-stimulated extracellular matrix invasion by the human melanoma low-affinity p75 neurotrophin receptor: melanoma p75 functions independently of trkA. Mol Biol Cell. 1993 Nov;4(11):1205–1216. doi: 10.1091/mbc.4.11.1205. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Holland D. R., Cousens L. S., Meng W., Matthews B. W. Nerve growth factor in different crystal forms displays structural flexibility and reveals zinc binding sites. J Mol Biol. 1994 Jun 10;239(3):385–400. doi: 10.1006/jmbi.1994.1380. [DOI] [PubMed] [Google Scholar]
  34. Ibáez C. F., Ebendal T., Barbany G., Murray-Rust J., Blundell T. L., Persson H. Disruption of the low affinity receptor-binding site in NGF allows neuronal survival and differentiation by binding to the trk gene product. Cell. 1992 Apr 17;69(2):329–341. doi: 10.1016/0092-8674(92)90413-7. [DOI] [PubMed] [Google Scholar]
  35. Ibáez C. F. Neurotrophic factors: from structure-function studies to designing effective therapeutics. Trends Biotechnol. 1995 Jun;13(6):217–227. doi: 10.1016/S0167-7799(00)88949-0. [DOI] [PubMed] [Google Scholar]
  36. Ibáez C. F. Structure-function relationships in the neurotrophin family. J Neurobiol. 1994 Nov;25(11):1349–1361. doi: 10.1002/neu.480251104. [DOI] [PubMed] [Google Scholar]
  37. Jing S., Tapley P., Barbacid M. Nerve growth factor mediates signal transduction through trk homodimer receptors. Neuron. 1992 Dec;9(6):1067–1079. doi: 10.1016/0896-6273(92)90066-m. [DOI] [PubMed] [Google Scholar]
  38. Johnson D., Lanahan A., Buck C. R., Sehgal A., Morgan C., Mercer E., Bothwell M., Chao M. Expression and structure of the human NGF receptor. Cell. 1986 Nov 21;47(4):545–554. doi: 10.1016/0092-8674(86)90619-7. [DOI] [PubMed] [Google Scholar]
  39. Kaplan D. R., Stephens R. M. Neurotrophin signal transduction by the Trk receptor. J Neurobiol. 1994 Nov;25(11):1404–1417. doi: 10.1002/neu.480251108. [DOI] [PubMed] [Google Scholar]
  40. Korsching S. The neurotrophic factor concept: a reexamination. J Neurosci. 1993 Jul;13(7):2739–2748. doi: 10.1523/JNEUROSCI.13-07-02739.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Large T. H., Weskamp G., Helder J. C., Radeke M. J., Misko T. P., Shooter E. M., Reichardt L. F. Structure and developmental expression of the nerve growth factor receptor in the chicken central nervous system. Neuron. 1989 Feb;2(2):1123–1134. doi: 10.1016/0896-6273(89)90179-7. [DOI] [PubMed] [Google Scholar]
  42. Lawrence M. C., Colman P. M. Shape complementarity at protein/protein interfaces. J Mol Biol. 1993 Dec 20;234(4):946–950. doi: 10.1006/jmbi.1993.1648. [DOI] [PubMed] [Google Scholar]
  43. Levi-Montalcini R., Skaper S. D., Dal Toso R., Petrelli L., Leon A. Nerve growth factor: from neurotrophin to neurokine. Trends Neurosci. 1996 Nov;19(11):514–520. doi: 10.1016/S0166-2236(96)10058-8. [DOI] [PubMed] [Google Scholar]
  44. 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. Science. 1996 Jul 26;273(5274):464–471. doi: 10.1126/science.273.5274.464. [DOI] [PubMed] [Google Scholar]
  45. Mahadeo D., Kaplan L., Chao M. V., Hempstead B. L. High affinity nerve growth factor binding displays a faster rate of association than p140trk binding. Implications for multi-subunit polypeptide receptors. J Biol Chem. 1994 Mar 4;269(9):6884–6891. [PubMed] [Google Scholar]
  46. Marchetti D., McQuillan D. J., Spohn W. C., Carson D. D., Nicolson G. L. Neurotrophin stimulation of human melanoma cell invasion: selected enhancement of heparanase activity and heparanase degradation of specific heparan sulfate subpopulations. Cancer Res. 1996 Jun 15;56(12):2856–2863. [PubMed] [Google Scholar]
  47. Matsumoto K., Wada R. K., Yamashiro J. M., Kaplan D. R., Thiele C. J. Expression of brain-derived neurotrophic factor and p145TrkB affects survival, differentiation, and invasiveness of human neuroblastoma cells. Cancer Res. 1995 Apr 15;55(8):1798–1806. [PubMed] [Google Scholar]
  48. McDonald N. Q., Lapatto R., Murray-Rust J., Gunning J., Wlodawer A., Blundell T. L. New protein fold revealed by a 2.3-A resolution crystal structure of nerve growth factor. Nature. 1991 Dec 5;354(6352):411–414. doi: 10.1038/354411a0. [DOI] [PubMed] [Google Scholar]
  49. Meakin S. O., Shooter E. M. The nerve growth factor family of receptors. Trends Neurosci. 1992 Sep;15(9):323–331. doi: 10.1016/0166-2236(92)90047-c. [DOI] [PubMed] [Google Scholar]
  50. Myers S. M., Ross G. M., Dostaler S. M., Anderson M. N., Weaver D. F., Riopelle R. J. Putative cytoplasmic amphiphilic domains in the nerve growth factor/tumour necrosis factor receptor superfamily. Biochim Biophys Acta. 1994 Nov 23;1196(1):21–28. doi: 10.1016/0005-2736(94)90290-9. [DOI] [PubMed] [Google Scholar]
  51. Naismith J. H., Devine T. Q., Kohno T., Sprang S. R. Structures of the extracellular domain of the type I tumor necrosis factor receptor. Structure. 1996 Nov 15;4(11):1251–1262. doi: 10.1016/s0969-2126(96)00134-7. [DOI] [PubMed] [Google Scholar]
  52. Naismith J. H., Sprang S. R. Modularity in the TNF-receptor family. Trends Biochem Sci. 1998 Feb;23(2):74–79. doi: 10.1016/s0968-0004(97)01164-x. [DOI] [PubMed] [Google Scholar]
  53. Persson H., Ibáez C. F. Role and expression of neurotrophins and the trk family of tyrosine kinase receptors in neural growth and rescue after injury. Curr Opin Neurol Neurosurg. 1993 Feb;6(1):11–18. [PubMed] [Google Scholar]
  54. Rabizadeh S., Oh J., Zhong L. T., Yang J., Bitler C. M., Butcher L. L., Bredesen D. E. Induction of apoptosis by the low-affinity NGF receptor. Science. 1993 Jul 16;261(5119):345–348. doi: 10.1126/science.8332899. [DOI] [PubMed] [Google Scholar]
  55. Radeke M. J., Misko T. P., Hsu C., Herzenberg L. A., Shooter E. M. Gene transfer and molecular cloning of the rat nerve growth factor receptor. Nature. 1987 Feb 12;325(6105):593–597. doi: 10.1038/325593a0. [DOI] [PubMed] [Google Scholar]
  56. Richards F. M. Areas, volumes, packing and protein structure. Annu Rev Biophys Bioeng. 1977;6:151–176. doi: 10.1146/annurev.bb.06.060177.001055. [DOI] [PubMed] [Google Scholar]
  57. Robinson R. C., Radziejewski C., Stuart D. I., Jones E. Y. Structure of the brain-derived neurotrophic factor/neurotrophin 3 heterodimer. Biochemistry. 1995 Apr 4;34(13):4139–4146. doi: 10.1021/bi00013a001. [DOI] [PubMed] [Google Scholar]
  58. Rodriguez-Tébar A., Dechant G., Barde Y. A. Binding of brain-derived neurotrophic factor to the nerve growth factor receptor. Neuron. 1990 Apr;4(4):487–492. doi: 10.1016/0896-6273(90)90107-q. [DOI] [PubMed] [Google Scholar]
  59. Rodríguez-Tébar A., Dechant G., Götz R., Barde Y. A. Binding of neurotrophin-3 to its neuronal receptors and interactions with nerve growth factor and brain-derived neurotrophic factor. EMBO J. 1992 Mar;11(3):917–922. doi: 10.1002/j.1460-2075.1992.tb05130.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Ross G. M., Shamovsky I. L., Lawrance G., Solc M., Dostaler S. M., Jimmo S. L., Weaver D. F., Riopelle R. J. Zinc alters conformation and inhibits biological activities of nerve growth factor and related neurotrophins. Nat Med. 1997 Aug;3(8):872–878. doi: 10.1038/nm0897-872. [DOI] [PubMed] [Google Scholar]
  61. Ross G. M., Shamovsky I. L., Lawrance G., Solc M., Dostaler S. M., Weaver D. F., Riopelle R. J. Reciprocal modulation of TrkA and p75NTR affinity states is mediated by direct receptor interactions. Eur J Neurosci. 1998 Mar;10(3):890–898. doi: 10.1046/j.1460-9568.1998.00094.x. [DOI] [PubMed] [Google Scholar]
  62. Rydén M., Hempstead B., Ibáez C. F. Differential modulation of neuron survival during development by nerve growth factor binding to the p75 neurotrophin receptor. J Biol Chem. 1997 Jun 27;272(26):16322–16328. doi: 10.1074/jbc.272.26.16322. [DOI] [PubMed] [Google Scholar]
  63. Rydén M., Ibáez C. F. Binding of neurotrophin-3 to p75LNGFR, TrkA, and TrkB mediated by a single functional epitope distinct from that recognized by trkC. J Biol Chem. 1996 Mar 8;271(10):5623–5627. doi: 10.1074/jbc.271.10.5623. [DOI] [PubMed] [Google Scholar]
  64. Rydén M., Murray-Rust J., Glass D., Ilag L. L., Trupp M., Yancopoulos G. D., McDonald N. Q., Ibáez C. F. Functional analysis of mutant neurotrophins deficient in low-affinity binding reveals a role for p75LNGFR in NT-4 signalling. EMBO J. 1995 May 1;14(9):1979–1990. doi: 10.1002/j.1460-2075.1995.tb07190.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Singh J., Garber E., Van Vlijmen H., Karpusas M., Hsu Y. M., Zheng Z., Naismith J. H., Thomas D. The role of polar interactions in the molecular recognition of CD40L with its receptor CD40. Protein Sci. 1998 May;7(5):1124–1135. doi: 10.1002/pro.5560070506. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Snider W. D., Johnson E. M., Jr Neurotrophic molecules. Ann Neurol. 1989 Oct;26(4):489–506. doi: 10.1002/ana.410260402. [DOI] [PubMed] [Google Scholar]
  67. Thoenen H. The changing scene of neurotrophic factors. Trends Neurosci. 1991 May;14(5):165–170. doi: 10.1016/0166-2236(91)90097-e. [DOI] [PubMed] [Google Scholar]
  68. Timm D. E., Ross A. H., Neet K. E. Circular dichroism and crosslinking studies of the interaction between four neurotrophins and the extracellular domain of the low-affinity neurotrophin receptor. Protein Sci. 1994 Mar;3(3):451–458. doi: 10.1002/pro.5560030310. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Van der Zee C. E., Ross G. M., Riopelle R. J., Hagg T. Survival of cholinergic forebrain neurons in developing p75NGFR-deficient mice. Science. 1996 Dec 6;274(5293):1729–1732. doi: 10.1126/science.274.5293.1729. [DOI] [PubMed] [Google Scholar]
  70. Wang W., Dostaler S. M., Lawrence G., Ross G. M., Riopelle R. J., Dow K. E. Effects of a peptide analogue of the amphiphilic domain of the common neurotrophin receptor on nerve growth factor-mediated motility of human neuroblastoma cells. J Neurochem. 1998 Jun;70(6):2327–2335. doi: 10.1046/j.1471-4159.1998.70062327.x. [DOI] [PubMed] [Google Scholar]
  71. Washiyama K., Muragaki Y., Rorke L. B., Lee V. M., Feinstein S. C., Radeke M. J., Blumberg D., Kaplan D. R., Trojanowski J. Q. Neurotrophin and neurotrophin receptor proteins in medulloblastomas and other primitive neuroectodermal tumors of the pediatric central nervous system. Am J Pathol. 1996 Mar;148(3):929–940. [PMC free article] [PubMed] [Google Scholar]
  72. Yan H., Chao M. V. Disruption of cysteine-rich repeats of the p75 nerve growth factor receptor leads to loss of ligand binding. J Biol Chem. 1991 Jun 25;266(18):12099–12104. [PubMed] [Google Scholar]

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