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.
Suga
Kei
K
Department of Cell Physiology, Kyorin University School of Medicine, Mitaka, Tokyo, Japan. ksuga@kyorin-u.ac.jp
Saito
Ayako
A
Tomiyama
Takami
T
Mori
Hiroshi
H
Akagawa
Kimio
K
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