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

Abstract

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

Copper and zinc ions govern the trans‐directed dimerization of APP family members in multiple ways

“…These data suggest that APLP2 trans-directed dimerization is modulated in a fashion different from that of APP and APLP1, implying distinct structural features of APLP2. In line with this, recent structural data analyses of the APLP2 E2 domain also suggest distinct dimerization properties for APLP2 (Roisman et al 2019).…”

“…In line with this, recent structural data analyses of the APLP2 E2 domain also suggest distinct dimerization properties for APLP2 (Roisman et al . ).…”

The acute phase protein lactoferrin is a key feature of Alzheimer’s disease and predictor of Aβ burden through induction of APP amyloidogenic processing

“…S10A ). B Model of holo-Lf binding sites (coloured as shown in ( A )) overlaid on the APP-E2 structure [ 97 ]. C Potency of the holo-Lf binding peptides of APP was assessed by dose dependently pre-incubating the peptide with holo-Lf (500 nM; 2 h) in vitro before adding to wt-APP 695 SH-SY5Y and evaluating sAPPβ secretion in the media after a further 2 h. wt-APP 695 SH-SY5Y exposure of APP peptide alone at each respective concentration showed no change in sAPPβ levels (data not shown).…”

Novel regulators of PrPCbiosynthesis revealed by genome-wide RNA interference

“…The ablation of APLP2 had no significant effect on incubation times of scrapie in mice (Tamgüney et al, 2008), suggesting that the upregulation of PrP C upon APLP2 knockdown may be specific to humans. Mechanistically, APLP2 might serve as a co-receptor for the endocytosis of PrP C , akin to what has been described for MHC class I molecules (Peters et al, 2013) Alternatively, the regulation of PrP C may be related to the role of APLP2 in metal homeostasis (Millhauser, 2004;Roisman et al, 2019). TMCC2 has been previously described as an ERresident molecule that interacts with APP and has an effect on metabolism of amyloid-β (Hopkins et al, 2011).…”