Abstract
The scaffolding protein family Fe65, composed of Fe65, Fe65L1, and Fe65L2, was identified as an interaction partner of the amyloid precursor protein (APP), which plays a key function in Alzheimer’s disease. All three Fe65 family members possess three highly conserved interaction domains, forming complexes with diverse binding partners that can be assigned to different cellular functions, such as transactivation of genes in the nucleus, modulation of calcium homeostasis and lipid metabolism, and regulation of the actin cytoskeleton. In this article, we rule out putative new intracellular signaling mechanisms of the APP-interacting protein Fe65 in the regulation of actin cytoskeleton dynamics in the context of various neuronal functions, such as cell migration, neurite outgrowth, and synaptic plasticity.
Highlights
The scaffolding protein family Fe65, composed of Fe65, Fe65L1, and Fe65L2, was identified as an interaction partner of the amyloid precursor protein (APP), which plays a key function in Alzheimer’s disease
APBB stands for APP-binding family B and refers to the observation that all three Fe65 proteins bind to the amyloid precursor protein (APP; Box 1) involved in the pathogenesis of Alzheimer’s disease (AD) [1,4,5,6,7,8,9]
At least six different isoforms have been reported for Fe65: Isoform 1, called p97Fe65, is the longest isoform with 710 amino acids; isoforms 2 and 3 lack two amino acids, E462 and R463, resulting from a deletion of mini-exon 9 [14]; isoforms 3, 5 and 6 have an N-terminal deletion of 240 amino acids and instead carrying a short N-terminal sequences of 6–20 amino acids derived from alternative start positions; isoform 4, called p60Fe65, is N-terminally truncated by 259 amino acids
Summary
The scaffolding protein family Fe65 is composed of Fe65 itself and two. Fe65-like proteins, Fe65L1 and Fe65L2. The amyloid precursor protein (APP) is a type I transmembrane protein with a large extracellular and a short intracellular domain It undergoes a complex proteolytic processing by sequential cleavage of different sheddases that cleave extracellular portions of transmembrane proteins, releasing the soluble ectodomains, followed by γ-secretase cleavage of the residual membrane tethered stub. Supplementary to the function of the secreted fragments, additional functions of full-length membrane-bound APP have been proposed as co-receptors for very different signaling pathways, involved in neurite outgrowth and synaptic plasticity. The molecular signaling of APP is not yet understood, genetic studies, considering the overlapping function of the two APP homologous proteins, APLP1 and APLP2, clearly showed an essential contribution in diverse cellular functions such as neuronal outgrowth, synaptic plasticity, and vesicular trafficking [23,24,25,26]
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