Human APP Intracellular Domain Complex with Fe65-PTB2: Difference between revisions
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'''Intracellular domain of human APP in complex with Fe65-PTB2''' | '''Intracellular domain of human APP in complex with Fe65-PTB2''' | ||
Cleavage of the amyloid precursor protein (APP) is a crucial event in Alzheimer disease pathogenesis that creates the amyloid-beta peptide (Abeta) and liberates the carboxy-terminal APP intracellular domain (AICD) into the cytosol. <ref>PMID 18833287</ref> The study of interaction of the AICD and Fe65 protein is rather important, as Fe65 protein seems to be implied in production of Abeta and in signalling in APP. | Cleavage of the amyloid precursor protein (APP) is a crucial event in Alzheimer disease pathogenesis that creates the amyloid-beta peptide (Abeta) and liberates the carboxy-terminal APP intracellular domain (AICD) into the cytosol. <ref>PMID:18833287</ref> The study of interaction of the AICD and Fe65 protein is rather important, as Fe65 protein seems to be implied in production of Abeta and in signalling in APP. | ||
{{STRUCTURE_3dxc | PDB=3dxc | SCENE= }} | {{STRUCTURE_3dxc | PDB=3dxc | SCENE= }} | ||
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This structure contains 4 chains. <scene name='SANDBOX138/Chainesaandc/1'>A chain is identical to C chain</scene>. Each contains 140 residues: 4 helices and 7 strands. It's a part of the protein Fe65 binded with APP intracellular domain. | This structure contains 4 chains. <scene name='SANDBOX138/Chainesaandc/1'>A chain is identical to C chain</scene>. Each contains 140 residues: 4 helices and 7 strands. It's a part of the protein Fe65 binded with APP intracellular domain. | ||
<scene name='SANDBOX138/Chains_bandd/1'>Chains B | <scene name='SANDBOX138/Chains_bandd/1'>Chains B and D are also identical</scene>. Each contains 35 residues: 2 helices and 1 strand. They represent APP intracellular domain. | ||
The crystal structure of the APP intracellular domain is in complex with the <scene name='SANDBOX138/Ptb/1'>C-terminal phosphotyrosine-binding (PTB) domain of Fe65</scene>. The interaction of the APP C terminus with the adaptor protein Fe65 mediates APP trafficking and signalling, and is thought to regulate APP processing and Abeta generation. The unique interface involves the NPxY PTB-binding motif and two alpha helices. The amino-terminal helix of the APP intracellular domain is | The crystal structure of the APP intracellular domain is in complex with the <scene name='SANDBOX138/Ptb/1'>C-terminal phosphotyrosine-binding (PTB) domain of Fe65</scene>. The interaction of the APP C terminus with the adaptor protein Fe65 mediates APP trafficking and signalling, and is thought to regulate APP processing and Abeta generation. The unique interface involves the NPxY PTB-binding motif and two alpha helices. The amino-terminal helix of the APP intracellular domain is | ||
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APP is a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis. APP is involved in cell mobility and transcription regulation through protein-protein interactions. Can promote transcription activation through binding to APBB1-KAT5 and inhibits Notch signaling through interaction with Numb. Couples to apoptosis-inducing pathways such as those mediated by G(O) and JIP. Inhibits G(o) alpha ATPase activity By similarity. Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1. Involved in copper homeostasis/oxidative stress through copper ion reduction. In vitro, copper-metallated APP induces neuronal death directly or is potentiated through Cu2+-mediated low-density lipoprotein oxidation. Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV. The splice isoforms that contain the BPTI domain possess protease inhibitor activity. | APP is a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis. APP is involved in cell mobility and transcription regulation through protein-protein interactions. Can promote transcription activation through binding to APBB1-KAT5 and inhibits Notch signaling through interaction with Numb. Couples to apoptosis-inducing pathways such as those mediated by G(O) and JIP. Inhibits G(o) alpha ATPase activity By similarity. Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1. Involved in copper homeostasis/oxidative stress through copper ion reduction. In vitro, copper-metallated APP induces neuronal death directly or is potentiated through Cu2+-mediated low-density lipoprotein oxidation. Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV. The splice isoforms that contain the BPTI domain possess protease inhibitor activity. | ||
Beta-amyloid peptides are lipophilic metal chelators with metal-reducing activity. Bind transient metals such as copper, zinc and iron. In vitro, can reduce Cu2+ and Fe3+ to Cu+ and Fe2+, respectively. Beta-amyloid 42 is a more effective reductant than beta-amyloid 40. Beta-amyloid peptides bind to lipoproteins and apolipoproteins E and J in the CSF and to HDL particles in plasma, inhibiting metal-catalyzed oxidation of lipoproteins. Beta-APP42 may activate mononuclear phagocytes in the brain and elicit inflammatory responses. Promotes both tau aggregation and TPK II-mediated phosphorylation. Interaction with overexpressed HADH2 leads to oxidative stress and neurotoxicity. <ref>6</ref> <ref>7</ref> <ref>8</ref> <ref> | Beta-amyloid peptides are lipophilic metal chelators with metal-reducing activity. Bind transient metals such as copper, zinc and iron. In vitro, can reduce Cu2+ and Fe3+ to Cu+ and Fe2+, respectively. Beta-amyloid 42 is a more effective reductant than beta-amyloid 40. Beta-amyloid peptides bind to lipoproteins and apolipoproteins E and J in the CSF and to HDL particles in plasma, inhibiting metal-catalyzed oxidation of lipoproteins. Beta-APP42 may activate mononuclear phagocytes in the brain and elicit inflammatory responses. Promotes both tau aggregation and TPK II-mediated phosphorylation. Interaction with overexpressed HADH2 leads to oxidative stress and neurotoxicity. <ref>6</ref> <ref>7</ref> <ref>8</ref> <ref>PMID: 19225519</ref> | ||
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== APP and Alzheimer disease == | == APP and Alzheimer disease == | ||
Aβ peptides are generated in neuronal secretory vesicles by proteolytic cleavage of the amyloid precursor protein (APP) by proteases, called β-secretase and γ-secretase that cleave at the N-terminus and variant C-termini of Aβ within APP, respectively, resulting in Aβ of 40 or 42 amino acids (Aβ40 and Aβ42, respectively) (Figure 1). Because the N-termini of Aβ40 and Aβ42 are identical, development of inhibitors that reduce cleavage of APP at the β-secretase site are likely to be effective for reducing Aβ peptide forms with alleviation of neurodegeneration and memory deficit. The APP in the vast majority of AD patients possesses the wild-type β-secretase site sequence. <ref> | Aβ peptides are generated in neuronal secretory vesicles by proteolytic cleavage of the amyloid precursor protein (APP) by proteases, called β-secretase and γ-secretase that cleave at the N-terminus and variant C-termini of Aβ within APP, respectively, resulting in Aβ of 40 or 42 amino acids (Aβ40 and Aβ42, respectively) (Figure 1). Because the N-termini of Aβ40 and Aβ42 are identical, development of inhibitors that reduce cleavage of APP at the β-secretase site are likely to be effective for reducing Aβ peptide forms with alleviation of neurodegeneration and memory deficit. The APP in the vast majority of AD patients possesses the wild-type β-secretase site sequence. <ref>PMID:2654319</ref> | ||
