Syntaxin 5 interacts specifically with presenilin holoproteins and affects processing of betaAPP in neuronal cells.
The specific roles of syntaxin 5 (Syx 5) in the interaction with presenilin (PS) and the accumulation of beta-amyloid precursor protein (betaAPP), as well as the secretion of beta-amyloid peptide (Abeta peptide) were examined in NG108-15 cells. Syx 5, which localizes from the endoplasmic reticulum (ER) to the Golgi, bound to PS holoproteins, while the other Syxs studied did not. Among familial Alzheimer's disease (FAD)-linked PS mutants, PS1deltaE9, which lacks the endoproteolytic cleavage site, showed markedly decreased binding to Syx 5. The interaction domains in Syx 5 were mapped to the transmembrane region and to the cytoplasmic region containing the alpha-helical domains, which are distinct from the H3 (SNARE motif). Among all of the Syxs examined, only overexpression of Syx 5 resulted in the accumulation of betaAPP in the ER to cis-Golgi compartment, an attenuation of the amount of the C-terminal fragment (APP-CTF) of betaAPP, and a reduction in the secretion of Abeta peptides. Furthermore, co-expression of Syx 5 with C99 resulted in an increase in APP-CTF and suppressed Abeta secretion. Taken together, these results indicate that Syx 5 may play a specific role in the modulation of processing and/or trafficking of FAD-related proteins in neuronal cells by interaction with PS holoproteins in the early secretory compartment of neuronal cells.
Department of Cell Physiology, Kyorin University School of Medicine, Mitaka, Tokyo, Japan. ksuga@kyorin-u.ac.jp
Kei
K
Suga
Ayako
A
Saito
Takami
T
Tomiyama
Hiroshi
H
Mori
Kimio
K
Akagawa
D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000494:pharmacology; D015153:Blotting, Western / Q000379:methods; D019556:COS Cells; D002451:Cell Compartmentation; D002522:Chlorocebus aethiops; D006224:Cricetinae; D004347:Drug Interactions; D010450:Endopeptidases; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D007150:Immunohistochemistry / Q000379:methods; D047468:Immunoprecipitation / Q000379:methods; D008565:Membrane Proteins / Q000145:classification / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D016296:Mutagenesis / Q000502:physiology; D009154:Mutation / Q000502:physiology; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010452:Peptide Biosynthesis / Q000502:physiology; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D010957:Plasmids / Q000502:physiology; D053764:Presenilin-1; D017434:Protein Structure, Tertiary / Q000502:physiology; D050765:Qa-SNARE Proteins; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014162:Transfection / Q000379:methods; D014280:Triglycerides / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000494:pharmacology
D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; D010446:Peptide Fragments; D053764:Presenilin-1; D050765:Qa-SNARE Proteins; D011993:Recombinant Fusion Proteins; D014280:Triglycerides; D005680:gamma-Aminobutyric Acid; C057077:1,2-dilinolenoyl-3-(4-aminobutyryl)propane-1,2,3-triol; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse