Modeled structure of the 75-kDa neurotrophin receptor

Chapman, Barbara S.; Kuntz, Irwin D.

doi:10.1002/pro.5560040905

Cited by 44 publications

(28 citation statements)

References 79 publications

(96 reference statements)

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“…7). An extended interface between p75 and northern plus southern contact points on NGF would be generally compatible with a hypothetical molecular model of the NGF⅐p75 complex (31).…”

Section: Figsupporting

confidence: 52%

The Role of the Nerve Growth Factor Carboxyl Terminus in Receptor Binding and Conformational Stability

Krüttgen¹,

Heymach

Kahle³

et al. 1997

Journal of Biological Chemistry

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The role of the nerve growth factor (NGF) carboxyl terminus in the function of NGF is not well understood. Previous work showed that deletion of residues 112-120 abolished NGF bioactivity. Several mutagenesis studies, however, have localized the binding sites of the two NGF receptors, p75 and TrkA, to other regions of the NGF molecule. To investigate the role of the NGF COOH terminus, we performed a detailed structure-function analysis of this region by deleting stepwise each of the nine COOH-terminal residues as well as constructing six point mutants. We found that point mutations within the 111-115 region, but not deletion of residues 116 -120, significantly decreased NGF bioactivity, as determined by TrkA tyrosine phosphorylation and neurite outgrowth from PC12 cells. Mutation of the absolutely conserved Leu 112 led to severely disrupted p75 binding on A875 cells but had only a modest effect on TrkA binding to MG87-TrkA fibroblasts. This suggests that the p75 binding surface is more extended than previously believed and includes not only charged residues within loops 1 and 5 but also spatially discontinuous, uncharged residues in a region where the NH 2 and COOH termini are in close proximity. Unexpectedly, deletion of COOH-terminal residues beyond Ala 116 led to significantly decreased stability. These results demonstrate that residues 111-115, but not residues 116 -120, are important for both the structural stability and biological activity of NGF.The neurotrophins are a family of survival and differentiation factors that exert a profound influence on development and maintenance of the nervous system (1). This feature makes neurotrophins promising candidates as therapeutic agents for the treatment of neurological disorders (2, 3). The crystal structure of the prototype neurotrophin, NGF, 1 revealed that it belongs to the cystine knot superfamily of structurally related growth factors (4). The well conserved "core" of the NGF molecule consists of two pairs of anti-parallel ␤-strands that form an elongated dimer interface and are held together by three disulfide bridges uniquely arranged in a characteristic cystine knot motif. The ␤-strands are connected to the "north" of the protomer by three ␤-hairpin loops, whereas the NH 2 and COOH termini appear to be located closer to the "south" of the protomers (see Fig. 7 for details). The loops and termini were not well resolved by x-ray crystallography and are thus likely to be highly flexible (5, 6). Moreover, these domains are regions of highest sequence divergence among neurotrophins. There is ample evidence for an involvement of these neurotrophin regions in specific receptor binding (7).Two NGF receptors have been identified: the p75 neurotrophin receptor and the tyrosine kinase TrkA (8 -10). Although TrkA is able to elicit NGF responses by itself in some systems, p75 can co-operate with TrkA to increase NGF binding to and activation of TrkA at low ligand concentration (11,12). Mutagenesis studies have previously demonstrated that the binding of NGF to p75 is ...

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“…7). An extended interface between p75 and northern plus southern contact points on NGF would be generally compatible with a hypothetical molecular model of the NGF⅐p75 complex (31).…”

Section: Figsupporting

confidence: 52%

The Role of the Nerve Growth Factor Carboxyl Terminus in Receptor Binding and Conformational Stability

Krüttgen¹,

Heymach

Kahle³

et al. 1997

Journal of Biological Chemistry

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“…The NTs act on receptive cells by binding to specific membrane receptors [Chao and Hempstead, 1995]. The low-affinity NT receptor p75 binds all NTs with similar affinity, whereas the high-affinity receptors, the tyrosine kinase (Trk) receptors, bind the NTs with different affinity, NGF binding to TrkA, BDNF and NT-4/5 binding to TrkB, and NT-3 binding to TrkC [Johnson et al, 1986;Martin-Zanca et al, 1989;Chapman and Kuntz, 1995]. The two NTs for which most information exists are NGF and BDNF.…”

mentioning

confidence: 99%

Expression Patterns of Neurotrophins and Neurotrophin Receptors in Articular Chondrocytes and Inflammatory Infiltrates in Knee Joint Arthritis

Grimsholm¹,

Guo

et al. 2008

Cells Tissues Organs

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Background: It is likely that neurotrophins (NTs) are of great importance for the articular cartilage and the inflammation process in arthritis. Methods: The immunohistochemical expression of the NTs nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) and the associated receptors p75, TrkA and TrkB was examined in the knee joint of arthritic and healthy mice. Results: Immunoreactions for NGF and BDNF were detected in cells and nerve fiber varicosities in the inflammatory infiltrates of the synovial tissue of arthritic joints but not in synovial tissue of controls. p75-immunoreactive nerve fiber-like strands were detected in inflammatory infiltrates. Immunostaining for NGF, BDNF, p75, TrkA and TrkB was noted in articular chondrocytes. There was a statistically significant decrease in reactions for NGF (p < 0.001), TrkA (p = 0.001) and p75 (p < 0.001) in articular chondrocytes in joints exhibiting severe arthritis. Conclusion: The findings show that an NT system develops in inflammatory infiltrates of the synovial tissue. Furthermore, most interestingly, autocrine/paracrine effects appear to exist concerning NTs for the articular chondrocytes. The downregulated expression of NGF and NT receptors in articular chondrocytes in arthritis is a new aspect concerning the involvement of NTs in cartilage.

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“…The significantly increased viability of NGF-treated cells was mediated by TrkA signaling because this effect could be antagonized by inhibition of the TrkA receptor. This blocking effect also ruled out the possibility that the observed effects of NGF were mediated by other receptors such as the low affinity pan-neurotrophin receptor p75 NTR , a well-known death-signaling receptor that acts through the JNK kinase pathway or through NF-B/RelA (42)(43)(44).…”

Section: Discussionmentioning

confidence: 99%

Nerve Growth Factor and Neurotrophin-3 Mediate Survival of Pulmonary Plasma Cells during the Allergic Airway Inflammation

Abram

Wegmann

Fokuhl

et al. 2009

The Journal of Immunology

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Allergen-specific Abs play a pivotal role in the induction and maintenance of allergic airway inflammation. During secondary immune responses, plasma cell survival and Ab production is mediated by extrinsic factors provided by the local environment (survival niches). It is unknown whether neurotrophins, a characteristic marker of allergic airway inflammation, influence plasma cell survival in the lung. Using a mouse model of allergic asthma, we found that plasma cells from the lung and spleen are distinct subpopulations exhibiting differential expression patterns of neurotrophins and their receptors (Trks). In vitro, the nerve growth factor (NGF) and neurotrophin-3 (NT3) led to a dose-dependent increase in viability of isolated pulmonary plasma cells due to up-regulation of the antiapoptotic Bcl2 pathway. In parallel, the expression of transcription factors that stimulate the production of immunoglobulins (X-box binding protein 1 and NF-B subunit RelA) was enhanced in plasma cells treated with NGF and NT3. These findings were supported in vivo. When the NGF pathway was blocked by intranasal application of a selective TrkA inhibitor, sensitized mice showed reduced numbers of pulmonary plasma cells and developed lower levels of allergen-specific and total serum IgE in response to OVA inhalation. This suggests that in the allergic airway inflammation, NGF/TrkA-mediated pulmonary IgE production contributes significantly to serum-IgE levels. We conclude that the neurotrophins NGF and NT3 act as survival factors for pulmonary plasma cells and thus are important regulators of the local Ab production in the allergic airway disease.

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Modeled structure of the 75-kDa neurotrophin receptor

Cited by 44 publications

References 79 publications

The Role of the Nerve Growth Factor Carboxyl Terminus in Receptor Binding and Conformational Stability

The Role of the Nerve Growth Factor Carboxyl Terminus in Receptor Binding and Conformational Stability

Expression Patterns of Neurotrophins and Neurotrophin Receptors in Articular Chondrocytes and Inflammatory Infiltrates in Knee Joint Arthritis

Nerve Growth Factor and Neurotrophin-3 Mediate Survival of Pulmonary Plasma Cells during the Allergic Airway Inflammation

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