Physiological relevance and dynamic regulation of APLP-mediated cell:cell interactions
Final Report Abstract
Biochemical, structural and functional cellular studies showed that zinc ions bound to APP and APLP1 E2 domains mediate oligomerization of these molecules, whereas the APLP2 E2 domain interacts more weakly with zinc possessing a less surfaceexposed zinc-binding site, and stayed monomeric. We found the effects mediated by a novel zinc-binding site within the APLP1 E2 domain, which we characterized by biochemical methods. The X-ray structure of the metal-bound E2 domain of APP containing four evolutionary highly conserved histidine residues was solved at 2.6-2.0 Å resolution. Cellular studies performed with the fluorescence resonance energy transfer (FRET) technique examined the effect in real time, showed that zinc ions specifically induce APP and APLP1 oligomerization and force APLP1 into multimeric clusters at the plasma membrane. We could conclude that zinc binding and APP/APLP oligomerization are intimately linked, regulate APP/APLP protein function and influence Aβ40 and Aβ42 levels. A conserved mechanism for specific HSPG recognition mediated by the E2 domain suggested a regulatory role of HSPG modifications in the biology of APP and APP-like proteins. Indeed, we found APP and APLP ligand zinc to modulate neuronal functions of APP and APLPs by (i) facilitating formation of adhesion complexes, most prominently for APLP1, and (ii) by reducing the concentrations of neurotrophic soluble APP/APLP ectodomains.
Publications
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(2012) Novel APP/Aβ mutation K16N produces highly toxic heteromeric Aβ oligomers. EMBO Mol Med, 4, 647-59
Kaden D, Harmeier A, Weise C, Munter LM, Althoff V, Rost BR, Hildebrand PW, Schmitz D, Schaefer M, Lurz R, Skodda S, Yamamoto R, Arlt S, Finckh U, Multhaup G
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(2012). APP dimer formation is initiated in the endoplasmic reticulum and differs between APP isoforms. Cell Mol Life Sci. 69, 1353-75
Isbert S, Wagner K, Eggert S, Schweitzer A, Multhaup G, Weggen S, Kins S, Pietrzik CU
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(2012). Metal binding dictates conformation and function of the amyloid precursor protein (APP) E2 domain. J Mol Biol, 416, 438-52
Dahms SO, Könnig I, Roeser D, Gührs KH, Mayer MC, Kaden D, Multhaup G, Than ME
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(2012). The amyloid precursor protein and its homologues: structural and functional aspects of native and pathogenic oligomerization. Eur J Cell Biol. 4, 234-9
Kaden D, Munter LM, Reif B, Multhaup G
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(2013). Meeting report: 7th Fabisch Symposium for Cancer Research and Molecular Cell Biology-regulated intramembrane proteolysis in cancer development and neurodegenerative diseases. Neurodegener Dis. 11, 215-8
Kaden D, Multhaup G
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(2014). Novel zinc-binding site in the E2 domain regulates amyloid precursor-like protein 1 (APLP1) oligomerization. J Biol Chem, 289, 19019-30
Mayer MC, Kaden D, Schauenburg L, Hancock MA, Voigt P, Roeser D, Barucker C, Than ME, Schaefer M, Multhaup G
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Amyloid precursor-like protein 1 (APLP1) exhibits stronger zinc-dependent neuronal adhesion than amyloid precursor protein and APLP2. J Neurochem. 2016 Apr;137(2):266-76
Mayer MC, Schauenburg L, Thompson-Steckel, G, Kaden D, Voigt P, Schaefer M, Chiantia, S, Kennedy, TE, Multhaup G
