Novel zinc-binding site in the E2 domain regulates amyloid precursor-like protein 1 (APLP1) oligomerization.
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Mayer MC, Kaden D, Schauenburg L, Hancock MA, Voigt P, Roeser D, Barucker C, Than ME, Schaefer M, Multhaup G
Novel zinc-binding site in the E2 domain regulates amyloid precursor-like protein 1 (APLP1) oligomerization.
J Biol Chem. 2014 Jul 4;289(27):19019-30. doi: 10.1074/jbc.M114.570382. Epub 2014 May 22.
- PubMed ID
- 24855651 [ View in PubMed]
- Abstract
The amyloid precursor protein (APP) and the APP-like proteins 1 and 2 (APLP1 and APLP2) are a family of multidomain transmembrane proteins possessing homo- and heterotypic contact sites in their ectodomains. We previously reported that divalent metal ions dictate the conformation of the extracellular APP E2 domain (Dahms, S. O., Konnig, I., Roeser, D., Guhrs, K.-H., Mayer, M. C., Kaden, D., Multhaup, G., and Than, M. E. (2012) J. Mol. Biol. 416, 438-452), but unresolved is the nature and functional importance of metal ion binding to APLP1 and APLP2. We found here that zinc ions bound to APP and APLP1 E2 domains and mediated their oligomerization, whereas the APLP2 E2 domain interacted more weakly with zinc possessing a less surface-exposed zinc-binding site, and stayed monomeric. Copper ions bound to E2 domains of all three proteins. Fluorescence resonance energy transfer (FRET) analyses examined the effect of metal ion binding to APP and APLPs in the cellular context in real time. Zinc ions specifically induced APP and APLP1 oligomerization and forced APLP1 into multimeric clusters at the plasma membrane consistent with zinc concentrations in the blood and brain. The observed effects were mediated by a novel zinc-binding site within the APLP1 E2 domain as APLP1 deletion mutants revealed. Based upon its cellular localization and its dominant response to zinc ions, APLP1 is mainly affected by extracellular zinc among the APP family proteins. We conclude that zinc binding and APP/APLP oligomerization are intimately linked, and we propose that this represents a novel mechanism for regulating APP/APLP protein function at the molecular level.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Copper Amyloid-like protein 1 Protein Humans UnknownCofactorDetails Zinc Amyloid beta A4 protein Protein Humans UnknownCofactorDetails Zinc Amyloid-like protein 1 Protein Humans UnknownCofactorDetails Zinc Amyloid-like protein 2 Protein Humans UnknownCofactorDetails Zinc acetate Amyloid beta A4 protein Protein Humans UnknownNot Available Details Zinc acetate Amyloid-like protein 1 Protein Humans UnknownNot Available Details Zinc acetate Amyloid-like protein 2 Protein Humans UnknownNot Available Details Zinc chloride Amyloid beta A4 protein Protein Humans UnknownLigandDetails Zinc chloride Amyloid-like protein 1 Protein Humans UnknownLigandDetails Zinc chloride Amyloid-like protein 2 Protein Humans UnknownLigandDetails Zinc sulfate, unspecified form Amyloid beta A4 protein Protein Humans UnknownLigandDetails Zinc sulfate, unspecified form Amyloid-like protein 1 Protein Humans UnknownLigandDetails Zinc sulfate, unspecified form Amyloid-like protein 2 Protein Humans UnknownLigandDetails