Specificity of neurotrophin-3 determined by loss-of-function mutagenesis

Abstract

Neurotrophin-3 (NT-3) is a member of the family of neurotrophic factors, which also includes nerve growth factor (NGF) and which have specific activities on different subsets of vertebrate neurons. The aim of this study was to determine which residues in NT-3 direct its specificity to the cognate TrkC receptor. It was possible to replace 80% of the residues in NT-3 with NGF residues without loss of specific activity. Residues D72, Y85, R87, W101, S107, and A111, together with either the residues F12, V18, V20, M37, V42, F54, and K57 or the variable regions IV and V, accounted for the specificity of NT-3. It is concluded that NGF and NT-3 use overlapping as well as separated regions for determination of specificities for their cognate receptors TrkA and TrkC, respectively.

HIV-1 infection and AIDS: consequences for the central nervous system

“…The figure is modified from Kaul and Lipton 199 HIV-1 infection and AIDS M Kaul et al neurotrophins are secreted by macrophages. 97 These factors include, but are not limited to, brain-derived neurotrophic factor (BDNF), 147 insulin-like growth factor (IGF)-2, 148 bnerve growth factor (bNGF), 149 transforming growth factor beta (TGF-b), 150 neurotrophin-3 (NT3) 151 and glial-derived neurotrophic factor (GDNF). 152 Clearly, a dysregulation of macrophage neurotrophic factors by viral infection and/or immune activation may occur during disease.…”

Molecular Basis of Neurotrophin−Receptor Interactions

“…Studies in these areas are at relatively early stages of development. One of the best ways to approach these issues is to consider data from crystallographic analyses of neurotrophins and their receptors (Table 1), 71,72,[74][75][76]78,[106][107][108] with mutagenesis studies to access loss-of-function effects (Table 2) [109][110][111][112][113][114][115][116][117][118][119][120][121][122] and gain-offunction approaches based on chimeric recombination of neurotrophins (Table 3). 93,112,117,[123][124][125] In loss-of-function approaches, individual residues or small fragments of neurotrophins are deleted, replaced with alanine (alanine scanning mutagenesis), or substituted with homologous sequences from another family member (i.e., "homologue scanning mutagenesis", in which case there is also a significant possibility of gainof-function).…”

HIV treatment: mechanisms of neurotoxicity and implications for targeted therapy

“…[189][190][191][192] Furthermore, a number of neurotrophins are normally secreted by macrophages, 193 eg, brain-derived neurotrophic factor, insulin-like growth factor, β-nerve growth factor, transforming growth factor-β, neurotrophin-3, neurotrophin-4/5, and glialderived neurotrophic factor. [194][195][196][197][198][199][200][201][202] Expression of these neurotrophins is affected by cytokines and growth factors. [203][204][205] For instance, acidic fibroblast growth factor induces higher IL-4, IL-10, and IL-13 levels, as well as expression of nerve growth factor and brain-derived neurotrophic factor in transected rat spinal cords.…”