Novel Zinc-binding Site in the E2 Domain Regulates Amyloid Precursor-like Protein 1 (APLP1) Oligomerization

Mayer, Magnus C.; Kaden, Daniela; Schauenburg, Linda; Hancock, Mark A.; Voigt, Philipp; Roeser, Dirk; Barucker, Christian; Than, Manuel E.; Schaefer, Michael; Multhaup, Gerhard

doi:10.1074/jbc.m114.570382

Cited by 23 publications

(64 citation statements)

References 72 publications

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“…3). Previous analysis, using Surface Plasmon Resonance, of copper and zinc binding to the APLP2, APP and APLP1 E2 domains demonstrated that both zinc and copper bind to all 3 E2 domains in a similar reversible and dose‐dependent manner (47).…”

Section: Resultsmentioning

confidence: 99%

“…This study completes the set of APP family E2 structures and will assist in our understanding of the structure: function relationships between the APP family members. A combination of biochemical, cellular, and whole‐animal studies indicates that APP, APLP1, and APLP2 have both shared and distinct activities in neuronal and nonneuronal tissues (2, 3, 5, 7, 10, 11, 22, 47, 51). Of these, APLP2 is essential for survival in the absence of the other APP family paralogues (3, 4, 10), which indicates that it possesses unique activities.…”

Section: Resultsmentioning

confidence: 99%

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The crystal structure of amyloid precursor‐like protein 2 E2 domain completes the amyloid precursor protein family

et al. 2019

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The amyloid precursor–like protein 2 (APLP2) molecule is a type I transmembrane protein that is crucial for survival, cell‐cell adhesion, neuronal development, myelination, cancer metastasis, modulation of metal, and glucose and insulin homeostasis. Moreover, the importance of the amyloid precursor protein (APP) family in biology and disease is very well known because of its central role in Alzheimer disease. In this study, we determined the crystal structure of the independently folded E2 domain of APLP2 and compared that with its paralogues APP and APLP2, demonstrating high overall structural similarities. The crystal structure of APLP2 E2 was solved as an antiparallel dimer, and analysis of the protein interfaces revealed a distinct mode of dimerization that differs from the previously reported dimerization of either APP or APLP1. Analysis of the APLP2 E2 metal binding sites suggested it binds zinc and copper in a similar manner to APP and APLP1. The structure of this key protein might suggest a relationship between the distinct mode of dimerization and its biologic functions.—Roisman, L. C., Han, S., Chuei, M. J., Connor, A. R., Cappai, R. The crystal structure of amyloid precursor‐like protein 2 E2 domain completes the amyloid precursor protein family. FASEB J. 33, 5076–5081 (2019). http://www.fasebj.org

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

The crystal structure of amyloid precursor‐like protein 2 E2 domain completes the amyloid precursor protein family

et al. 2019

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“…Indeed, it has been shown that the disulfide bond in the E1 domain might be the main contributor for trans-dimerization between APP molecules and its homologues [34, 58, 59, 72] , although the E2 domain could still account partially to enhance synaptic connections in the absence of E1 [77] . The importance of E1 and E2 domain interactions with APP and APP homologues has been confirmed [80, 81] . Based on the findings that endogenous APP and APLPs are rapidly processed by γ-secretase [82] and also the APP homologues differ in their extent to which they are cleaved by β-site APP cleaving enzyme 1 (BACE1) at the steady state in neurons (APLP1 is more readily cleaved relative to APP [83] ), only a subset of neuronal APP or APLPs may be available to transdimerize with adjacent cells or form cell surface receptor-like complexes.…”

Section: The Role Of App Subdomains In Dimerization Processmentioning

confidence: 99%

APP Receptor? To Be or Not To Be

Deyts

Wang

Parent

2016

Trends in Pharmacological Sciences

111

110

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Amyloid Precursor Protein (APP) and its metabolites play a critical role in Alzheimer’s disease pathogenesis. The idea that APP may function as a receptor has gained momentum based on its structural similarities to type I transmembrane receptors, and the identification of putative APP ligands. Here we review the recent experimental evidence in support of this notion and discuss how this concept is viewed in the field. Specifically, we focus on the structural and functional characteristics of APP as a cell surface receptor, and its interaction with adaptors and signaling proteins. We also address the importance of APP's function as a receptor in Alzheimer’s disease etiology and discuss how this function might be potentially important for the development of novel therapeutic approaches.

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“…the oligmerization behavior of the APP-orthologue APLP1 22 . In addition, the concentration of both metal ions has been shown to be largely altered in the brain interstitium during synaptic activity (reviewed in 23 ).…”

mentioning

confidence: 99%

Mutants of Metal Binding Site M1 in APP E2 Show Metal Specific Differences in Binding of Heparin but Not of sorLA

et al. 2015

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The amyloid precursor protein (APP) and its neurotoxic cleavage product Aβ are key players in the development of Alzheimer's disease (AD) and appear to be essential for neuronal development and cell homeostasis. Proteolytic processing of APP and its physiological function depend on its interaction with heparin and are influenced by the binding of metal ions and sorLA. We created various mutations of metal binding site M1 residing within the extracellular E2 domain of APP. Using isothermal titration calorimetry and circular dichroism spectroscopy, we analyzed the binding of Cu(2+) and Zn(2+) to APP E2 and identified two mutations that are most suited for functional studies to dissect ion specific effects of metal binding. The H313A mutation abrogates only copper-based effects, whereas the H382A mutation weakens any metal binding at M1 of APP E2. Subsequently, we tested the effect of Cu(2+) and Zn(2+) on the binding of heparin and sorLA to APP E2 using a chromatographic technique and surface plasmon resonance. We show that Zn(2+) and to a larger degree also Cu(2+) enhance the binding of heparin to APP E2, consistent with an extracellular regulation of the function of APP by both metal ions. In contrast, neither ion seemed to affect the interaction between APP E2 and sorLA. This supports an intracellular interaction between the latter two partners that would not sense extracellular variations of metal ions upon synaptic activity.

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Novel Zinc-binding Site in the E2 Domain Regulates Amyloid Precursor-like Protein 1 (APLP1) Oligomerization

Cited by 23 publications

References 72 publications

The crystal structure of amyloid precursor‐like protein 2 E2 domain completes the amyloid precursor protein family

The crystal structure of amyloid precursor‐like protein 2 E2 domain completes the amyloid precursor protein family

APP Receptor? To Be or Not To Be

Mutants of Metal Binding Site M1 in APP E2 Show Metal Specific Differences in Binding of Heparin but Not of sorLA

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