Hormone Mimicry

Wells, J.A.

doi:10.1126/science.273.5274.449

Cited by 57 publications

(35 citation statements)

References 24 publications

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“…The Trk subdomains identified in this study may be receptor functional "hot spots," a concept proposed for other receptors (34,35,39). Trk receptor signaling, the identification of multiple binding subdomains for the neurotrophins, and the regulation of subdomain utilization by receptors and ligands raises the possibility of a complex, multistage process whose study will give a better understanding of neurotrophin structureactivity relationships and signal transduction.…”

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confidence: 70%

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p75 Co-receptors Regulate Ligand-dependent and Ligand-independent Trk Receptor Activation, in Part by Altering Trk Docking Subdomains

Zaccaro¹,

Ivanisevic²,

Pérez³

et al. 2001

Journal of Biological Chemistry

122

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Neurotrophins signal via Trk tyrosine kinase receptors and a common receptor called p75. Nerve growth factor is the cognate ligand for TrkA, brain-derived neurotrophic factor for TrkB, and neurotrophin-3 (NT-3) for TrkC. NT-3 also binds TrkA and TrkB as a heterologous ligand. All neurotrophins bind p75, which regulates ligand affinity and Trk signals. Trk extracellular domain has five subdomains: a leucine-rich motif, two cysteinerich clusters, and immunoglobulin-like subdomains IgG-C1 and IgG-C2. The IgG-C1 subdomain is surface exposed in the tertiary structure and regulates ligandindependent activation. The IgG-C2 subdomain is less exposed but regulates cognate ligand binding and Trk activation. NT-3 as a heterologous ligand of TrkA and TrkB optimally requires the IgG-C2 but also binds other subdomains of these receptors. When p75 is co-expressed, major changes are observed; NGF-TrkA activation can occur also via the cysteine 1 subdomain, and brain-derived neurotrophic factor-TrkB activation requires the TrkB leucine-rich motif and cysteine 2 subdomains. We propose a two-site model of Trk binding and activation, regulated conformationally by the IgG-C1 subdomain. Moreover, p75 affects Trk subdomain utilization in ligand-dependent activation, possibly by conformational or allosteric control.

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confidence: 70%

“…5B). The conformational effect on the architecture may occur at the surface-exposed IgG-C1 subdomain, which could "rotate", as described for other receptors (34,35,39).…”

mentioning

confidence: 96%

p75 Co-receptors Regulate Ligand-dependent and Ligand-independent Trk Receptor Activation, in Part by Altering Trk Docking Subdomains

Zaccaro¹,

Ivanisevic²,

Pérez³

et al. 2001

Journal of Biological Chemistry

122

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“…While it is well established that physiological ligands activate signal transduction by inducing receptor dimerization, allosteric models of receptor activation have also been proposed (15,(32)(33)(34)(35)(36). There are two major obstacles to studying allosteric models experimentally.…”

Section: And 5)mentioning

confidence: 99%

“…Ligands docking onto restricted receptor pockets or "hot spots" are presumed to be more efficient at mediating (ant)agonistic function (34,44). Reportedly, there are at least two activating TrkA "hot spots" (45)(46)(47)(48) encompassing the IgC-2-like domain and the leucinerich motif.…”

Section: And 5)mentioning

confidence: 99%

Genuine Monovalent Ligands of TrkA Nerve Growth Factor Receptors Reveal a Novel Pharmacological Mechanism of Action

Maliartchouk¹,

Debeir²,

Beglova³

et al. 2000

Journal of Biological Chemistry

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Developing small molecule agonistic ligands for tyrosine kinase receptors has been difficult, and it is generally thought that such ligands require bivalency. Moreover, multisubunit receptors are difficult to target, because each subunit contributes to ligand affinity, and each subunit may have distinct and sometimes opposing functions. Here, the nerve growth factor receptor subunits p75 and the tyrosine kinase TrkA were studied using artificial ligands that bind specifically to their extracellular domain. Bivalent TrkA ligands afford robust signals. However, genuine monomeric and monovalent TrkA ligands afford partial agonism, activate the tyrosine kinase activity, cause receptor internalization, and induce survival and differentiation in cell lines and primary neurons. Monomeric and monovalent TrkA ligands can synergize with ligands that bind the p75 subunit. However, the p75 ligands used in this study must be bivalent, and monovalent p75 ligands have no effect. These findings will be useful in designing and developing screens of small molecules selective for tyrosine kinase receptors and indicate that strategies for designing agonists of multisubunit receptors require consideration of the role of each subunit. Last, the strategy of using anti-receptor mAbs and small molecule hormone mimics as receptor ligands could be applied to the study of many other heteromeric cell surface receptors.

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“…If the choice is to construct a monovalent library, the fusion virion partner should be protein III since each virion has 5 to 6 copies of them (14) and the fusion particle would display 1 to 3 fusion molecules (13). Recent studies have proposed the use of multivalent libraries for initial screening experiments and in a second step, when refined ligands are desired, the monovalent libraries would be the choice (15).…”

Section: Introductionmentioning

confidence: 99%

Expression of anti-Z-DNA single chain antibody variable fragment on the filamentous phage surface

Maranhão

Brígido

2000

Braz J Med Biol Res

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We describe the expression of an anti-Z-DNA single chain variable region antibody fragment (scFv) on a filamentous phage surface. Four vectors for phage display were constructed. Two of them are able to display multiple copies of the antibody fragment, and the others can be used to make monovalent libraries. The vectors use different promoter/leader sequences to direct the expression of the fused proteins. All were able to promote the assembly of fusion virion particles. In this paper we also show the affinity selection (biopanning) of those phageantibodies based on the capacity of their products to recognize the antigen. We used biotinylated Z-DNA and the selection was performed in a solution phase fashion. The data presented here indicate that these vectors can be further used to construct anti-nucleic acid antibody fragment libraries that can be used to study the basis of nucleic acid-protein interaction and its role in autoimmunity mechanisms.

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Hormone Mimicry

Cited by 57 publications

References 24 publications

p75 Co-receptors Regulate Ligand-dependent and Ligand-independent Trk Receptor Activation, in Part by Altering Trk Docking Subdomains

p75 Co-receptors Regulate Ligand-dependent and Ligand-independent Trk Receptor Activation, in Part by Altering Trk Docking Subdomains

Genuine Monovalent Ligands of TrkA Nerve Growth Factor Receptors Reveal a Novel Pharmacological Mechanism of Action

Expression of anti-Z-DNA single chain antibody variable fragment on the filamentous phage surface

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