title: Secreted human amyloid precursor protein binds semaphorin 3a and prevents semaphorin-induced growth cone collapse.
abstract: The amyloid precursor protein (APP) is well known for giving rise to the amyloid-β peptide and for its role in Alzheimer's disease. Much less is known, however, on the physiological roles of APP in the development and plasticity of the central nervous system. We have used phage display of a peptide library to identify high-affinity ligands of purified recombinant human sAPPα(695) (the soluble, secreted ectodomain from the main neuronal APP isoform). Two peptides thus selected exhibited significant homologies with the conserved extracellular domain of several members of the semaphorin (Sema) family of axon guidance proteins. We show that sAPPα(695) binds both purified recombinant Sema3A and Sema3A secreted by transfected HEK293 cells. Interestingly, sAPPα(695) inhibited the collapse of embryonic chicken (Gallus gallus domesticus) dorsal root ganglia growth cones promoted by Sema3A (K(d)≤8·10(-9) M). Two Sema3A-derived peptides homologous to the peptides isolated by phage display blocked sAPPα binding and its inhibitory action on Sema3A function. These two peptides are comprised within a domain previously shown to be involved in binding of Sema3A to its cellular receptor, suggesting a competitive mechanism by which sAPPα modulates the biological action of semaphorins.
authors.affiliation: Institute of Medical Biochemistry, Program in Biochemistry and Cellular Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. magdesian@bioqmed.ufrj.br
authors.forename: Margaret H
authors.initials: MH
authors.lastname: Magdesian
authors.forename: Matthias
authors.initials: M
authors.lastname: Gralle
authors.forename: Luiz H
authors.initials: LH
authors.lastname: Guerreiro
authors.forename: Paulo José I
authors.initials: PJ
authors.lastname: Beltrão
authors.forename: Milena M V F
authors.initials: MM
authors.lastname: Carvalho
authors.forename: Luís Eduardo da S
authors.initials: LE
authors.lastname: Santos
authors.forename: Fernando G
authors.initials: FG
authors.lastname: de Mello
authors.forename: Ricardo A M
authors.initials: RA
authors.lastname: Reis
authors.forename: Sérgio T
authors.initials: ST
authors.lastname: Ferreira
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D002642:Chick Embryo; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism*; D020439:Growth Cones / Q000502:physiology*; D006801:Humans; D047468:Immunoprecipitation; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D019151:Peptide Library; D011487:Protein Conformation; D040121:Semaphorin-3A / Q000378:metabolism*
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D017077:Culture Media, Conditioned; D010446:Peptide Fragments; D019151:Peptide Library; D040121:Semaphorin-3A