Review
The amyloid precursor protein and its homologues: Structural and functional aspects of native and pathogenic oligomerization

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Abstract

Over the last 25 years, remarkable progress has been made not only in identifying key molecules of Alzheimer's disease but also in understanding their meaning in the pathogenic state. One hallmark of Alzheimer pathology is the amyloid plaque. A major component of the extracellular deposit is the amyloid-β (Aβ) peptide which is generated from its larger precursor molecule, i.e., the amyloid precursor protein (APP) by consecutive cleavages. Processing is exerted by two enzymes, i.e., the β-secretase and the γ-secretase. We and others have found that the self-association of the amyloid peptide and the dimerization and oligomerization of these proteins is a key factor under native and pathogenic conditions. In particular, the homodimer represents a nidus for plaque formation and a well defined therapeutic target. Further, dimerization of the APP was reported to increase generation of toxic Aβ whereas heterodimerization with its homologues amyloid precursor like proteins (APLP1 and APLP2) decreased Aβ formation. This review mainly focuses on structural features of the homophilic and heterophilic interactions among APP family proteins. The proposed contact sites are described and the consequences of protein dimerization on their functions and in the pathogenesis of Alzheimer's disease are discussed.

Introduction

It became widely accepted that the proteolytic processing of APP is a central event in the onset of Alzheimer's disease. Following the initial ectodomain shedding of APP by ADAM10 (a disintegrin and metalloprotease, also known as α-secretase) or BACE1 (β-site APP cleaving enzyme, also β-secretase), the remaining membrane-bound C-terminal stubs are degraded by the γ-secretase complex. This process has been named regulated intramembrane proteolysis (RIP) (reviewed in De Strooper, 2010). The concerted action of BACE1 and γ-secretase leads to the generation of Aβ peptides. Soluble oligomers of Aβ are regarded as the toxic agent and are most likely responsible for neurodegeneration observed in Alzheimer's disease (Harmeier et al., 2009, Schmechel et al., 2003, Walsh et al., 2002). APP processing by the α-secretase creates the soluble APP ectodomain (sAPPα), which exerts neuroprotective activities (Furukawa et al., 1996, Mattson, 1997, Small et al., 1994). Insulin and insulin growth factor-1 (IGF-1) have been shown to increase α-secretase cleavage of APP as well as the ectodomain shedding of the APP-like proteins APLP1 and APLP2 in human neuroblastoma (SH-SY5Y) cells (Adlerz et al., 2007, Jacobsen et al., 2010). Accumulating evidence suggests that APP and its homologous proteins APLP1 and APLP2 are capable of forming homo- and heterodimers in living cells with a direct impact on APP processing and Aβ generation (Kaden et al., 2008, Kaden et al., 2009, Munter et al., 2007). The APP family proteins are type I transmembrane proteins with a large, glycosylated extracellular domain and a short conserved cytoplasmic tail. For APP, dimerization likely occurs as early as in the endoplasmic reticulum and follows a zipper-like mechanism starting from the N to the C terminus involving multiple contact sites. Three different interaction sites are described in the literature, two reside in the ectodomain and one in the transmembrane sequence (TMS) (Beher et al., 1996, Kaden et al., 2008, Munter et al., 2007, Rossjohn et al., 1999, Soba et al., 2005, Wang and Ha, 2004). The physiological functions of APP are still not understood in detail, however, a functional role in cell development, cell–cell and/or cell–matrix interaction is likely. Oligomerization of cell surface receptors and activation in response to ligands is a common mechanism to transfer signals across the cell membrane. A proper signal recognition and such a transduction could not be verified for APP yet although it had been postulated when the full-length form of the molecule was first published (Kang et al., 1987). The Notch receptor is a substrate of the same set of proteases and the Notch intracellular domain (NICD) exhibits important signaling functions in neural development (for review see Woo et al., 2009). However, for Notch dimerization it could not be shown to be decisive for processing (Vooijs et al., 2004).

Section snippets

Structural features of APP and APLP

The APP family proteins contain different domains as shown in Fig. 1A. The linker domains are supposed to be unstructured and their main function is to ensure the flexibility of the other individual domains. In this review, we will discuss structural aspects and proposed functions of the E1 and E2 domains, the ectodomain as such, the transmembrane part and the cytoplasmic domain as the structures help to understand the dimerization processes important for Aβ generation.

The E1 and E2 domains

The E1 domain of APP (residues 18–207) contains two independent folding units, the growth factor-like domain (GFLD, 28–123) and the copper-binding domain (CuBD, 127–188) (Barnham et al., 2003, Rossjohn et al., 1999, Small et al., 1994). The crystal structure of the APP GFLD revealed a highly charged basic surface that was supposed to interact with glycosaminoglycans and a hydrophobic surface that being important for ligand binding (Rossjohn et al., 1999). Furthermore, the crystal structure

The ectodomain

There are only few data on the structure of the APP ectodomain as a whole and most are based on small angle X-ray scattering (SAXS) modeling. Conflicting data about dimerization exist for soluble APP generated by ADAM10 cleavage (sAPPα). While we found the APP ectodomain (sAPPα) purified from Pichia pastoris dimerizes in solution by cross-linking and size-exclusion chromatography, others only described sAPP monomers, or rather found dimers only in the presence of heparin (Gralle et al., 2002,

The transmembrane region and the Aβ sequence

The Aβ peptide encompasses the N-terminal juxtamembrane region (28 amino acid residues) as well as half of the TMS (Fig. 1B). Amyloid plaques purified from brain tissue contain mostly aggregated Aβ peptides. In the past few years, it turned out that oligomeric intermediate states, not the fibrillar end-products of the aggregation process are responsible for the neurotoxic effects that Aβ exerts in vivo (Hartley et al., 1999). Recently, several attempts to characterize the structure of these

The cytoplasmic domains and their role in signaling

The cytoplasmatic tail of APP comprises 47 amino acid residues containing a YENPTY sequence with a proposed dual function. On the one hand, the NPxY motif is a common signal for endocytosis and is necessary for the internalization of APP (Lai et al., 1995). On the other hand, the sequence mediates binding to various interacting partners, like Fe65 and X11 (summarized in Jacobsen and Iverfeldt, 2009). In aqueous solutions, the cytoplasmatic domain shows only transiently structured regions (

The APP protein family

Studies with APP and APLP1 knockout mice have revealed partially redundant functions of the APP family proteins. Whereas all single knockouts are viable and fertile, the double knockouts of APP/APLP2 and APLP1/APLP2 are perinatally lethal (Heber et al., 2000, von Koch et al., 1997, Zheng et al., 1995) suggesting that APLP2 is functionally important and unique within the APP protein family. The APP/APLP1 double knockout is also viable and fertile and no grossly changed phenotype was observed (

Conclusion

Oligomerization is a key factor in the regulation of proteins in general and especially in Alzheimer's disease as non-native oligomers of Aβ peptides are associated with the pathogenic states. Key molecules in the development of Alzheimer's disease natively oligomerize, i.e. substrates (APP and APLPs) and the enzymes BACE1 and γ-secretase (not discussed in this review). Although there is an ongoing discussion if the APP ectodomain and the single domains dimerize in solution, it is quite clear

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