Identification and Structure of the Nerve Growth Factor Binding Site on TrkA

Identification and Structure of the Nerve Growth Factor Binding Site on TrkA

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...

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Bibliographic Details
Published in:Biochemical and biophysical research communications Vol. 282; no. 1; pp. 131 - 141
Main Authors: Robertson, Alan G.S., Banfield, Mark J., Allen, Shelley J., Dando, Julie A., Mason, Grant G.F., Tyler, Sue J., Bennett, Gavin S., Brain, Susan D., Clarke, Anthony R., Naylor, Ruth L., Wilcock, Gordon K., Brady, R.Leo, Dawbarn, David
Format: Journal Article
Language:English
Published: United States Elsevier Inc 23-03-2001
Subjects:
Alzheimer's disease
Animals
Base Sequence
binding domain
Binding Sites
Capillary Permeability
Chromatography, Ion Exchange
Circular Dichroism
Crystallography, X-Ray
DNA Primers
Enzyme-Linked Immunosorbent Assay
Male
Nerve Growth Factor - metabolism
NGF/TrkA
PC12 Cells
Protein Conformation
Rats
Rats, Wistar
Receptor, trkA - chemistry
Receptor, trkA - metabolism
Recombinant Proteins - chemistry
Recombinant Proteins - metabolism
X-ray structure
NGF/TrkA
binding domain
X-ray structure
Alzheimer's disease
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Summary: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 (TrkAIg2) 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 TrkAIg2 domain in a new crystal form, refined to 2.0 Å resolution.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
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content type line 23
ISSN:0006-291X
1090-2104
DOI:10.1006/bbrc.2001.4462