Specificity of neurotrophin-3 determined by loss-of-function mutagenesis.
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.
Kullander
K
K
Department of Developmental Neuroscience, Uppsala University, Sweden. Klas.Kullander@mun.uu.se
Kylberg
A
A
Ebendal
T
T
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001921:Brain / Q000196:embryology / Q000378:metabolism; D002478:Cells, Cultured; D002642:Chick Embryo; D005728:Ganglia, Sympathetic / Q000166:cytology / Q000502:physiology; D015723:Gene Library; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009412:Nerve Fibers / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D009414:Nerve Growth Factors / Q000096:biosynthesis / Q000737:chemistry* / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D020933:Neurotrophin 3; D016133:Polymerase Chain Reaction; D011487:Protein Conformation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000502:physiology; D020801:Receptor, Ciliary Neurotrophic Factor; D020917:Receptor, trkA; D017475:Receptors, Nerve Growth Factor / Q000096:biosynthesis / Q000502:physiology; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000494:pharmacology; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
D009414:Nerve Growth Factors; D020933:Neurotrophin 3; D011518:Proto-Oncogene Proteins; D020801:Receptor, Ciliary Neurotrophic Factor; D017475:Receptors, Nerve Growth Factor; D011994:Recombinant Proteins; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA