Abstract
Mutations in presenilin 1 and 2 (PS1 and PS2) account for the majority of early-onset familial Alzheimer's disease (FAD). However, trafficking and interaction of PSs with other proteins are poorly understood. We have previously shown that PSs bound to syntaxin 5 (Syx5), which is a t-SNARE (target-soluble N-ethylmaleimide-sensitive factor-attachment protein receptor) that is involved in ER-Golgi vesicular transport. By using co-immunoprecipitation and pull down studies, we further examined the interaction of PS with Syx isoforms expressed in HeLa, COS7 and NG108-15 cells. We found that ER-type isoform of Syx5 bound to holoproteins of PS1 and PS2. In contrast, Syx1A, 2, 3 and 4 that are located at the plasma membrane did not show specific binding to PS. In addition, Syx6, 7, 8 that localized in post-TGN (trans-Golgi-Network) did not bind to PS holoproteins. The FAD-linked PS1 variant (PS1deltaE9), which lacks the cytoplasmic loop that contains the endoproteolytic cleavage site, showed markedly decreased binding to Syx5. Interaction domains in PS were mapped to the cytoplasmic loop region and transmembrane domain (TMD). The interaction domains in Syx5 were mapped to the TMD and the cytoplasmic region that is distinct from SNARE motif. Taken together, these results indicate that Syx5 isoforms specifically bind to full-length PSs at ER and cis-Golgi compartment via interaction of their cytoplasmic and transmembrane regions. These results suggest that Syx5 isoforms may play a role in trafficking PSs from the ER to the Golgi in the early secretory pathway. [Jpn J Physiol 54 Suppl:S86 (2004)]
