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. 2014;1(2):id1008.

Cycle on Wheels: Is APP Key to the AppBp1 Pathway?

Y Chen  1 , Rn Neve  2 , H Zheng  3 , Wts Griffin  4 , Sw Barger  5 , Re Mrak
Affiliations

Cycle on Wheels: Is APP Key to the AppBp1 Pathway?

Y Chen et al. Austin Alzheimers Parkinsons Dis. 2014.

Abstract

Alzheimer's disease (AD) is the gradual loss of the cognitive function due to neuronal death. Currently no therapy is available to slow down, reverse or prevent the disease. Here we analyze the existing data in literature and hypothesize that the physiological function of the Amyloid Precursor Protein (APP) is activating the AppBp1 pathway and this function is gradually lost during the progression of AD pathogenesis. The AppBp1 pathway, also known as the neddylation pathway, activates the small ubiquitin-like protein nedd8, which covalently modifies and switches on Cullin ubiquitin ligases, which are essential in the turnover of cell cycle proteins. Here we discuss how APP may activate the AppBp1 pathway, which downregulates cell cycle markers and protects genome integrity. More investigation of this mechanism-driven hypothesis may provide insights into disease treatment and prevention strategies.

Keywords: APP; Alzheimer's disease; Cell cycle; Neddylation; Ubiquitination.

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Figures

Figure 1
Figure 1. APP binds to AppBp1 in a region that mediates adenylation and nedd8 binding to NAE
A. C-terminal sequence of APP695 showing the C-terminus of Aβ40 and Aβ42, lysine residues (purple) that can be neddylated and the AppBp1 binding sites in APP AICD region (yellow lines). B. Diagram of conserved domains between NAE and Uba1. The APP-binding site, AppBp1 (145-251) as indicated was identified by Chow et al. [28]. The domains in AppBp1, Uba3, and Uba1 are drawn based on Schulman and Harper's review [38].
Figure 2
Figure 2. Schematic of neddylation, ubiquitination and proteasomal degradation
In the neddylation pathway, Mg++ATP and nedd8 bind NAE nucleotide binding site, react to yield nedd8-AMP, and release inorganic pyrophosphate. Nedd8-AMP then react with the thiol of the NAE active site cysteine, form the NAE-nedd8 thioester, and release AMP. A second ATP and nedd8 bind AppBp1/Uba3 to form nedd8-AMP, resulting in the fully loaded complex containing two nedd8 molecules, covalently bound nedd8 thioester and nedd8-AMP that occupies the NAE adenylation domain. This form of NAE activates the transfer of nedd8 to the conjugating enzyme by a transthiolation reaction. Subsequently, nedd8 is covalently attached to a Cullin in a lysine residue in the conserved Cullin domain. Neddylation of the Cullin activates the Cullin ubiquitin ligase. In the ubiquitination pathway, Uba1 functions similarly to NAE, but activates ubiquitin, which is ligated to target proteins when Cullin ubiquitin ligase are activated by neddylation. A Cul1 ubiquitin ligase complex (purple) known as SCF complex, is given as an example. The SCF complex consists of the zinc-finger protein, which binds to the C-terminus of Cul1, the adaptor protein Skp1, which binds to the N-terminus of Cul1. The substrate β-catenin is recruited by a specific F-box protein βTrCP1. The ubiquitin chain is recognized by the 26S proteasome, which leads to proteasomal degradation.
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