Molecular Basis of Neurotrophin−Receptor Interactions

Pattarawarapan, Mookda; Burgess, Kevin

doi:10.1021/jm030221q

Cited by 75 publications

(58 citation statements)

References 152 publications

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“…Biologically active BDNF exists as a homodimer held together by hydrophobic interactions, and the TrkB and p75 receptors engage both monomers in a homodimeric pair (10,37,38). Thus, we next assessed the preservation of the dimerization interface among the most favorable mutants, K8 and P10, on the yeast surface.…”

Section: Resultsmentioning

confidence: 99%

Directed Evolution of Brain-Derived Neurotrophic Factor for Improved Folding and Expression in Saccharomyces cerevisiae

Burns

Malott

Metcalf

et al. 2014

Appl Environ Microbiol

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cBrain-derived neurotrophic factor (BDNF) plays an important role in nervous system function and has therapeutic potential. Microbial production of BDNF has resulted in a low-fidelity protein product, often in the form of large, insoluble aggregates incapable of binding to cognate TrkB or p75 receptors. In this study, employing Saccharomyces cerevisiae display and secretion systems, it was found that BDNF was poorly expressed and partially inactive on the yeast surface and that BDNF was secreted at low levels in the form of disulfide-bonded aggregates. Thus, for the purpose of increasing the compatibility of yeast as an expression host for BDNF, directed-evolution approaches were employed to improve BDNF folding and expression levels. Yeast surface display was combined with two rounds of directed evolution employing random mutagenesis and shuffling to identify BDNF mutants that had 5-fold improvements in expression, 4-fold increases in specific TrkB binding activity, and restored p75 binding activity, both as displayed proteins and as secreted proteins. Secreted BDNF mutants were found largely in the form of soluble homodimers that could stimulate TrkB phosphorylation in transfected PC12 cells. Site-directed mutagenesis studies indicated that a particularly important mutational class involved the introduction of cysteines proximal to the native cysteines that participate in the BDNF cysteine knot architecture. Taken together, these findings show that yeast is now a viable alternative for both the production and the engineering of BDNF.

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Section: Resultsmentioning

confidence: 99%

Directed Evolution of Brain-Derived Neurotrophic Factor for Improved Folding and Expression in Saccharomyces cerevisiae

Burns

Malott

Metcalf

et al. 2014

Appl Environ Microbiol

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“…Interestingly, the neo cells lacking p75 NTR exhibited a NGF-induced increase in NFnB activity and P-JNK expression. Since NGF can bind the TrkA receptor, a tyrosine kinase capable of promoting growth and survival signals [1,35], the induction of transcriptional effectors in the neo cells by NGF may have occurred via the TrkA receptor. Conversely, p75 NTR is regarded as a growth suppressor and inducer of apoptosis, independent of ligand [12,36].…”

Section: Discussionmentioning

confidence: 99%

The p75NTR mediates a bifurcated signal transduction cascade through the NFκB and JNK pathways to inhibit cell survival

Allen

Khwaja

Byers

et al. 2005

Experimental Cell Research

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“…Neurotrophins are produced in precursor forms known as pro-neurotrophins with subsequent proteolytic processing to mature forms. Mature neurotrophin proteins contain three β-hairpin loops (loops 1, 2, and 4) that play key roles in mediating receptor interactions [4]. Neurotrophins bind to Trk tyrosine kinase receptors (NGF with TrkA, BDNF with TrkB and NT-3 primarily with TrkC) and to the common neurotrophin receptor known as p75 NTR .…”

Section: Functions Of Neurotrophin Receptorsmentioning

confidence: 99%

“…Peptide mimetics of NGF loop 1 generated the first evidence that compounds mimicking specific neurotrophin domains could interact with neurotrophin receptors to inhibit, activate or augment receptor signaling [29,30]. Additional peptide mimetics of various domains of NGF, BDNF and NT-3 have been found to interact with either p75 NTR or their cognate Trk receptors and modulate receptor signaling [4,[26][27][28]. The finding that NGF loop 1 synthetic peptide mimetics act via p75 NTR to prevent death of DRG sensory neurons [30] has lead to studies in which preliminary data suggests that NGF loop 1 mimetics activate PI3K/AKT signaling and prevent death of cultured hippocampal neurons.…”

Section: Development Of Neurotrophin Receptor Small Molecule Ligandsmentioning

confidence: 99%

Neurotrophin Receptor-Based Strategies for Alzheimers Disease

Longo

Massa²

2005

CAR

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The traditional perspective of applying neurotrophins in the context of Alzheimer's disease is based on the premise that neurotrophins are capable of upregulating cholinergic function and of rendering neurons less vulnerable to certain processes causing degeneration. Factors limiting the therapeutic application of neurotrophin proteins include their poor pharmacological properties and their pleiotropic effects mediated by interaction with Trk, p75NTR and sortilin receptors. Recent studies suggesting and that pro-forms of neurotrophins accumulating in Alzheimer's and other pathological states cause cell death, that p75NTR modulates amyloid beta- and injury-induced neurodegeneration and that small molecules can be created that bind specifically to individual neurotrophin receptors point to novel strategies by which neurotrophin receptors might be targeted in Alzheimer's and other neuropathological states.

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Molecular Basis of Neurotrophin−Receptor Interactions

Cited by 75 publications

References 152 publications

Directed Evolution of Brain-Derived Neurotrophic Factor for Improved Folding and Expression in Saccharomyces cerevisiae

Directed Evolution of Brain-Derived Neurotrophic Factor for Improved Folding and Expression in Saccharomyces cerevisiae

The p75NTR mediates a bifurcated signal transduction cascade through the NFκB and JNK pathways to inhibit cell survival

Neurotrophin Receptor-Based Strategies for Alzheimers Disease

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