Sandbox Reserved 591: Difference between revisions
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==Structure== | ==Structure== | ||
The extracellular region is separated into the E1 and E2 domains which are linked by an acidic domain. Over 70 percent of the amino acid residues of this region are involved with standard secondary structure elements. APP is a type I transmembrane that separates the large N-terminal extracellular domain from the short C-terminal cytoplasmic tail domain. The N-terminal, crystalized in 1999, contains nine beta-strands and only one alpha-helix. The domain has a surplus of cysteine and has three disulfide bridges and a hydrophobic core which together are well conserved throughout the APP family. The disulfide bridge between Cys98 and Cys105 stabilizes a β-hairpin loop which appears to be essential for neurite development and MAP kinase activation. This surface possibly represents one of the APP heparin-binding sites. Although, the β-hairpin loop is the most mobile area in this structure. <ref>PMID:3254787</ref>. Adjacent to this heparin structure is a hydrophobic surface patch which is critical in protein-protein interactions. The N-terminal head domain of APP has nothing in common with any other known protein. Since this structure can initiate neurite growth, some scientists think the N-terminal head domain alone is responsible for growth-factor like characteristics of APP. However, further exploration is needed to confirm this hypothesis. <ref>PMID:1356301</ref>. | The extracellular region is separated into the E1 and E2 domains which are linked by an acidic domain. Over 70 percent of the amino acid residues of this region are involved with standard secondary structure elements. APP is a type I transmembrane that separates the large N-terminal extracellular domain from the short C-terminal cytoplasmic tail domain. The N-terminal, crystalized in 1999, contains nine beta-strands and only one alpha-helix. The domain has a surplus of cysteine and has three disulfide bridges and a hydrophobic core which together are well conserved throughout the APP family. The disulfide bridge between Cys98 and Cys105 stabilizes a β-hairpin loop which appears to be essential for neurite development and MAP kinase activation. This surface possibly represents one of the APP heparin-binding sites. Although, the β-hairpin loop is the most mobile area in this structure. <ref>PMID:3254787</ref>. Adjacent to this heparin structure is a hydrophobic surface patch which is critical in protein-protein interactions. The N-terminal head domain of APP has nothing in common with any other known protein. Since this structure can initiate neurite growth, some scientists think the N-terminal head domain alone is responsible for growth-factor like characteristics of APP. However, further exploration is needed to confirm this hypothesis. <ref>PMID:1356301</ref>. | ||
The cytoplasmic (intracellular) domain is released by a γ-secretase-dependent mechanism. Most known binding partners of APP interact with the intracellular domain. One of the most important is the YENPTY motif which is present in the AICD. This motif is important for Clathrin-mediated endocytosis and binding to many proteins like Fe65 and JIP. It seems that the release of AICD can contribute to intracellular variations in the cytoskeleton formation or kinase localization, and might even cause indirect effects on nuclear transcription. <ref>O'Brien, Richard J. 2011. Amyloid Precursor Protein Processing and Alzheimer’s Disease. NIH. 34: 185–204. </ref> [[Image:79_app-rasmol.jpg|thumb|left|350px|APP Protein|Figure 1 APP Protein Structure in Two Guises]] | The cytoplasmic (intracellular) domain is released by a γ-secretase-dependent mechanism. Most known binding partners of APP interact with the intracellular domain. One of the most important is the YENPTY motif which is present in the AICD. This motif is important for Clathrin-mediated endocytosis and binding to many proteins like Fe65 and JIP. It seems that the release of AICD can contribute to intracellular variations in the cytoskeleton formation or kinase localization, and might even cause indirect effects on nuclear transcription. <ref>O'Brien, Richard J. 2011. Amyloid Precursor Protein Processing and Alzheimer’s Disease. NIH. 34: 185–204. </ref> [[Image:79_app-rasmol.jpg|thumb|left|350px|APP Protein|''Figure 1'' APP Protein Structure in Two Guises (PDB, 2013)]] | ||
== Function == | == Function == | ||
APP controls cholesterol turnovers needed for activity in the neurons. Some studies have even shown that it plays a role in memory deficiencies that many patients with AD experience. <ref>PMID:23495999</ref>. Most studies show overexpression of APP has effects on cell growth and health. The N-terminal heparin-binding domain of APP has been shown to stimulate neurite growth and promote synaptogenesis. Studies have also revealed that APP is able to regulate stem cells. APP plays a major role in the nervous system involved with synaptic plasticity. It also is key in maintaining neuronal calcium homeostasis which is important for transmitting synapses. <ref>PMID:23495999</ref>. One of the earliest indications of APP function came from analyzing the growth pattern of fibroblasts in which APP levels were lessened by expression of an antisense APP construct. These cells grew slowly, but the growth retardation could be restored by treatment with APPs. Along with the pentapeptide domain (RERMS), the infusion APPs into the brain | APP controls cholesterol turnovers needed for activity in the neurons. Some studies have even shown that it plays a role in memory deficiencies that many patients with AD experience. <ref>PMID:23495999</ref>. Most studies show overexpression of APP has effects on cell growth and health. The N-terminal heparin-binding domain of APP has been shown to stimulate neurite growth and promote synaptogenesis. Studies have also revealed that APP is able to regulate stem cells. APP plays a major role in the nervous system involved with synaptic plasticity. It also is key in maintaining neuronal calcium homeostasis which is important for transmitting synapses. <ref>PMID:23495999</ref>. One of the earliest indications of APP function came from analyzing the growth pattern of fibroblasts in which APP levels were lessened by expression of an antisense APP construct. These cells grew slowly, but the growth retardation could be restored by treatment with APPs. Along with the pentapeptide domain (RERMS), the infusion APPs into the brain | ||
