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TrkA receptor "hot spots" for binding of NT-3 as a heterologous ligand
Ivanisevic L.2; Zheng W.1; Woo S.B.3; Neet K.E.3; Saragovi H.U.2
2007-06-08
Source PublicationJournal of Biological Chemistry
ISSN00219258 1083351X
Volume282Issue:23Pages:16754-16763
AbstractNeurotrophins signal via Trk tyrosine kinase receptors. Nerve growth factor (NGF) is the cognate ligand for TrkA, the brain-derived neurotrophic factor for TrkB, and NT-3 for TrkC. NT-3 also binds TrkA as a lower affinity heterologous ligand. Because neurotrophin-3 (NT-3) interactions with TrkA are biologically relevant, we aimed to define the TrkA "hot spot" functional docking sites of NT-3. The Trk extracellular domain consists of two cysteine-rich subdomains (D1 and D3), flanking a leucine-rich subdomain (D2), and two immunoglobulin-like subdomains IgC1(D4) and IgC2(D5). Previously, the D5 subdomain was defined as the primary ligand-binding site of neurotrophins for their cognate receptors (e.g. NGF binds and activates through TRKA-D5 hot spots). Here binding studies with truncated and chimeric extracellular subdomains show that TRKA-D5 also includes an NT-3 docking and activation hot spot (site 1), and competition studies show that the NGF and NT-3 hot spots on TRKA-D5 are distinct but partially overlapping. In addition, ligand binding studies provide evidence for an NT-3-binding/allosteric site on TRKA-D4 (site 2). NT-3 docking on sites 1 and/or 2 partially blocks NGF binding. Functional survival studies showed that sites 1 and 2 regulate TrkA activation. NT-3 docking on both sites 1 and 2 affords full agonism, which can be additive with NGF activation of Trk. However, NT-3 docking solely on site 1 is partially agonistic but noncompetitively antagonizes NGF binding and activation of Trk. This study demonstrates that Trk signaling is more complex than previously thought because it involves several receptor subdomains and hot spots. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.
DOI10.1074/jbc.M701996200
URLView the original
Language英語
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Cited Times [WOS]:31   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionUniversity of Macau
Affiliation1.McGill University
2.Lady Davis Institute for Medical Research
3.Rosalind Franklin University of Medicine and Science
Recommended Citation
GB/T 7714
Ivanisevic L.,Zheng W.,Woo S.B.,et al. TrkA receptor "hot spots" for binding of NT-3 as a heterologous ligand[J]. Journal of Biological Chemistry,2007,282(23):16754-16763.
APA Ivanisevic L.,Zheng W.,Woo S.B.,Neet K.E.,&Saragovi H.U..(2007).TrkA receptor "hot spots" for binding of NT-3 as a heterologous ligand.Journal of Biological Chemistry,282(23),16754-16763.
MLA Ivanisevic L.,et al."TrkA receptor "hot spots" for binding of NT-3 as a heterologous ligand".Journal of Biological Chemistry 282.23(2007):16754-16763.
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