Neurotrophin

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Function

Neurotrophins (NT) are survival factors for sympathetic and sensory neurons and control a number of aspects of survival, development and function of neurons in the central and peripheral nervous systems[1]. There are 4 mammalian NTs and they are activated by the family of the receptor tyrosine kinases TrkA (see High affinity nerve growth factor receptor), TrkB (see TrkB tyrosine kinase receptor), TrkC. NTs activate the p75 neurotrophin receptor (BDNF) which is a member of the tumor necrosis factor receptor superfamily.

  • Neurotrophin 3 is released through the regulated secretory pathway and influences the development of the enteric nervous system[2].
  • Neurotrophin 4 is released through the constitutive secretory pathway [3].

Relevance

Alterations in NTs levels were implicated in neurodegenerative disorders such as Alzheimer disease and Huntington disease as well as psychiatric disorders including depression and substance abuse[4].

Structural highlights

The complex between NT3 and p75 neurotrophin receptor (p75NTR) shows a homodimer of NT3 with two symmetrically arranged p75NTR molecules. There are 3 sites of interactions between NT3 and p75NTR - site 1, site 2 and site 3[5].

  • Site 1.
  • Site 2.
  • Site 3.

Glycosylated human NT3 homodimer (cyan and green) complex with p75NTR (pink and yellow) (PDB code 3buk)

Drag the structure with the mouse to rotate

3D structures of neurotrophin

Updated on 17-July-2024

1b8k, 1nt3 – hNT3 – human
3buk – hNT3 + P75NTR
1bnd – hNT3 139-257 + BDNF
1b98 – hNT4 81-210
1b8m, 1hcf – hNT4 81-210 + BDNF

References

  1. Facci L, Skaper SD. Culture of rat cerebellar granule neurons and application to identify neuroprotective agents. Methods Mol Biol. 2012;846:23-37. doi: 10.1007/978-1-61779-536-7_3. PMID:22367798 doi:http://dx.doi.org/10.1007/978-1-61779-536-7_3
  2. Chalazonitis A. Neurotrophin-3 in the development of the enteric nervous system. Prog Brain Res. 2004;146:243-63. PMID:14699968 doi:10.1016/S0079-6123(03)46016-0
  3. Hibbert AP, Morris SJ, Seidah NG, Murphy RA. Neurotrophin-4, alone or heterodimerized with brain-derived neurotrophic factor, is sorted to the constitutive secretory pathway. J Biol Chem. 2003 Nov 28;278(48):48129-36. PMID:12970359 doi:10.1074/jbc.M300961200
  4. Chao MV, Rajagopal R, Lee FS. Neurotrophin signalling in health and disease. Clin Sci (Lond). 2006 Feb;110(2):167-73. doi: 10.1042/CS20050163. PMID:16411893 doi:http://dx.doi.org/10.1042/CS20050163
  5. Gong Y, Cao P, Yu HJ, Jiang T. Crystal structure of the neurotrophin-3 and p75NTR symmetrical complex. Nature. 2008 Aug 7;454(7205):789-93. Epub 2008 Jul 2. PMID:18596692 doi:10.1038/nature07089

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Michal Harel, Alexander Berchansky

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