Anextended surface ofbinding toTrktyrosine kinase receptors inNGFandBDNFallows theengineering ofa multifunctional pan-neurotrophin

cell survival anddifferentiation ofvertebrate neurons iscaused byligand-specific binding totheTrkfamily oftyrosine kinase receptors. However, sites intheneurotrophins responsible forthebinding to Trkreceptors andthemechanisms whereby this interaction results inreceptor activation andbiological activity areunknown. Hereweshowthat innerve growth factor (NGF)andbrain-derived neurotrophic factor (BDNF), discontinuous stretches ofaminoacidresidues group together ononeside oftheneurotrophin dimerforming a continuous surface responsible forbinding toand activation ofTrkAandTrkBreceptors. Twosymmetrical surfaces areformed alongthetwo-fold axisofthe neurotrophin dimerproviding a modelforligandmediated receptor dimerization. Mutated neurotrophins inducing similar levels ofreceptor phosphorylation showeddifferent biological activities, suggesting that structural differences inaligand mayresult indissimilar responses inagiven tyrosine kinase receptor. Ourresults allowed ustocombine structural elements fromNGF, BDNF andneurotrophin-3 toengineer a pan-neurotrophin thatefficiently activates allTrkreceptors and displays multiple neurotrophic specificities.