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Two restricted sites on the surface of the NGF molecule independently determine specific TrkA receptor binding and activation
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
1997 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 272, no 14, 9300-9307 p.Article in journal (Refereed) Published
Abstract [en]

Nerve growth factor (NGF) and neurotrophin-3 (NT-3) mediate activities such as survival, differentiation, and proliferation in various subsets of neurons. In this report, we define precisely the residues in human NGF responsible for NGF biological activity and binding specificity to the neurotrophin receptor TrkA. In earlier studies we defined five amino acid residues of NGF which confer NGF-like activity to NT-3 when replacing corresponding residues in the 120-amino acid long NT-3 molecule. Using this gain-of-function strategy we report the further dissection of this functional epitope. We also define another motif separated topographically in the NGF dimer and determined to be independently responsible for NGF specificity. The first of the two motifs determined to elicit NGF specificity is defined by the residues Val-48, Pro-49, and Gln-96, which are situated in the two top beta-loops of NGF. The second motif is represented by residues Pro-5 and Phe-7 situated in the proximal part of the NH2 terminus. Both motifs contain structurally important residues revealing a novel principle, where specificity for neurotrophin ligand-receptor interactions could be determined by variable residues modifying the conformation of the neurotrophin backbone. These findings will enhance further the possibility of mimicking NGF with low molecular weight compounds.

Place, publisher, year, edition, pages
1997. Vol. 272, no 14, 9300-9307 p.
National Category
Medical and Health Sciences
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URN: urn:nbn:se:uu:diva-56199DOI: 10.1074/jbc.272.14.9300PubMedID: 9083066OAI: oai:DiVA.org:uu-56199DiVA: diva2:84107
Available from: 2008-10-17 Created: 2008-10-17 Last updated: 2017-12-04Bibliographically approved

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