f sortilin in APP trafficking 
and distribution, and the underlying molecular mechanisms. We found that 10760364 1) sortilin is associated with APP via head-to-head and 17689526 tail-to-tail interactions; and 2) sortilin regulates APP lysosomal and lipid raft trafficking through FLVHRY motif. 10 Sortilin Regulates APP Trafficking and Processing The Interaction between Sortilin and APP is Important for APP Intracellular Distribution Including Lysosomal Targeting and the Distribution in Lipid Rafts Our results show that sortilin is involved in APP intracellular distribution via the interaction between sortilin and APP. Our mapping study has defined that sortilin interacts with APP through each ICD and ECD. The sortilin N-terminal binding site in ECD to APP is identified within amino acid 78-385, which contains part of the Vps10p domain. However, the Vps10p domain of SorLA has shown no interaction with APP, suggesting this binding site is unique to sortilin. Since SorLA has been reported to interact with APP via the luminal domain and the cytoplasmic tail, it is suggested that sortilin is likely to have a second binding site to APP. Indeed, we have identified that the sortilin C-terminal binding site to APP is FLVHRY belonging to the F/ YXXXXF/Y motif because the deletion of the FLVHRY abolishes the interaction between sortilin-ICD and APP-ICD. Given the fact that the F/YXXXXF/Y motif exists in SorLA and acts as an internalization/sorting signal in mannose-6 phosphate and low-density lipoprotein receptors, this interaction between APP and the FLVHRY motif highlights the potentially important role of sortilin in APP trafficking and processing. This is further supported by our in vivo and in vitro data which shows an altered distribution of APP in lysosomes and lipid rafts in neurons of sortilin KO mice, and in HEK293 cells co-expressing the sortilin MS1 deletion constructs. The APP-NPXYKFFE motif is likely to be responsible for the C’-terminal interaction with sortilin FLVHRY, because mutation of the NPXYKFFE motif eliminates this interaction. Recent reports have shown that mutant YKFFE motif is associated with redistribution of intracellular APP, which could be a result of the disruption of the interaction between sortilin FLVHRY and APP NPXYKFFE. It is possible that the sortilin-ICD is involved in controlling the fate of intracellular APP. Phosphorylation of APP at T668, located 14 amino acids toward the N-terminal end from the 681GYENPTY687 motif, has been reported to regulate the Sortilin Regulates APP Trafficking and Processing interaction of the 681GYENPTY687 motif with other MedChemExpress AEB-071 binders, suggesting that the phosphorylation may be involved in the interaction between sortilin FLVHRY and APP NPXYKFFE. The NPXYKFFE, containing a core NPXpY element, mediates APP internalization as well as the interaction between the proteins bearing phosphotyrosine-binding domains . There is evidence to suggest that JIP is associated with the kinesin-1 motor. Sortilin also interacts with HAP1, a protein interacting with the p150glued subunit of dynactin, which regulates neurotrophin axonal trafficking. The interactions between these proteins can facilitate appropriate APP axonal transport and is important to sort APP into the non-amyloidgenic pathway. Further studies are warranted to determine if the phosphorylation of APP at T668 plays a crucial role in the interaction with sortilin FLVHRY and if the N-terminal binding site of sortilin to APP has any roles in APP trafficking a