Cell
Volume 69, Issue 2, 17 April 1992, Pages 329-341
Journal home page for Cell

Article
Disruption of the low affinity receptor-binding site in NGF allows neuronal survival and differentiation by binding to the trk gene product

https://doi.org/10.1016/0092-8674(92)90413-7Get rights and content

Abstract

Nerve growth factor (NGF), like many other growth factors and hormones, binds to two different receptor molecules on responsive cells. The product of the proto-oncogene trk, p140trk, is a tyrosine kinase receptor that has been identified as a signal-transducing receptor for NGF, while the role of the low affinity NGF receptor, p75NGFR, in signal transduction is less clear. The crystal structure of NGF has recently been determined, although structures involved in receptor binding and biological activity are unknown. Here we show that Lys-32, Lys-34, and Lys-95 form a positively charged interface involved in binding to p75NGFR. Simultaneous modification of Lys-32 with either of the two other lysines resulted in loss of binding to p75NGFR. Despite the lack of binding to p75NGFR, these mutants retained binding to p140trk and biological activity, demonstrating a functional dissociation between the two NGF receptors.

References (70)

  • S.O. Meakin et al.

    Molecular investigations on the high-affinity nerve growth factor receptor

    Neuron

    (1991)
  • A. Rodriguez-Tébar et al.

    Binding of brain-derived neurotrophic factor to the nerve growth factor receptor

    Neuron

    (1990)
  • A. Rosenthal et al.

    Primary structure and biological activity of a novel human neurotrophic factor

    Neuron

    (1990)
  • A. Sutter et al.

    Nerve growth factor receptors: characterization of two distinct classes of binding sites on chick embryo sensory ganglia cells

    J. Biol. Chem.

    (1979)
  • G. Weskamp et al.

    Evidence that biological activity of NGF is mediated through a novel subclass of high affinity receptors

    Neuron

    (1991)
  • S.R. Whittemore et al.

    The expression, localization and functional significance of beta-nerve growth factor in the central nervous system

    Brain Res.

    (1987)
  • Y.-C. Yang et al.

    Human IL-3 (multi-CSF): identification by expression cloning of a novel hematopoietic growth factor related to murine IL-3

    Cell

    (1986)
  • R.H. Angeletti et al.

    Nerve growth factor from mouse submaxillary gland: amino acid sequence

  • R.H. Angeletti et al.

    Amino acid sequences of 2.5S nerve growth factor. II. Isolation and characterization of the thermolytic and peptic peptides and the complete covalent structure

    Biochemistry

    (1973)
  • S.P. Banerjee et al.

    Binding of nerve growth factor in superior cervical ganglia

  • Y.-A. Barde et al.

    Purification of a new neurotrophic factor from mammalian brain

    EMBO J.

    (1982)
  • M. Berg et al.

    The low-affinity p75 nerve growth factor (NGF) receptor mediates NGF-induced tyrosine phosphorylation

  • S.E. Buxser et al.

    Purification of the receptor for nerve growth factor from A875 melanoma cells by affinity chromatography

    J. Biol. Chem.

    (1983)
  • F. Carriero et al.

    Structure and expression of the nerve growth factor gene in Xenopus oocytes and embryos

    Mol. Reprod. Dev.

    (1991)
  • B.C. Cunningham et al.

    High-resolution epitope mapping of hGH-receptor interactions by alanine-scanning mutagenesis

    Science

    (1989)
  • T. Curran et al.

    Isolation and characterization of the c-fos (rat) cDNA and analysis of post-translational modification in vitro

    Oncogene

    (1987)
  • T. Ebendal

    Nerve growth factor promoting activities in embryonic and adult tissues

  • T. Ebendal

    Use of collagen gels to bioassay nerve growth factor activity

  • T. Ebendal et al.

    Structure and expression of the chicken β nerve growth factor

    EMBO J.

    (1986)
  • T. Ebendal et al.

    Characterization of antibodies to synthetic nerve growth factor (NGF) and proNGF peptides

    J Neurosci. Res.

    (1989)
  • P. Ernfors et al.

    Molecular cloning and neurotrophic activities of a protein with structural similarities to β-nerve growth factor: developmental and topographical expression in the brain

  • E. Gizang-Ginsberg et al.

    Nerve growth factor regulates tyrosine hydroxylase gene transcription through a nucleoprotein complex that contains c-Fos

    Genes Dev.

    (1990)
  • L.A. Greene et al.

    Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor

  • F. Hallböök et al.

    Expression of nerve growth factor receptor mRNA during early development of the chicken embryo: emphasis on cranial ganglia

    Development

    (1990)
  • B.L. Hempstead et al.

    Expression of functional nerve growth factor receptors after gene transfer

    Science

    (1989)
  • Cited by (0)

    View full text