Human APP Intracellular Domain Complex with Fe65-PTB2: Difference between revisions
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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 | ||
<scene name='SANDBOX138/T668/2'>capped by threonine T(668)</scene>, it's an Alzheimer disease-relevant phosphorylation site which is involved in Fe65-binding regulation. The structure together with mutational studies, isothermal titration calorimetry and nuclear magnetic resonance experiments sets the stage for understanding T(668) phosphorylation-dependent complex regulation at a molecular level.<ref>PMID 18833287</ref> Mutation at Thr-668 of APP abolished the effect of Fe65 on APP maturation. This mutation blocked the Fe65-dependent suppression of Abeta production and resulted in the release of increased levels of Abeta in the presence of Fe65 <ref>PMID: 11517218</ref> . | <scene name='SANDBOX138/T668/2'>capped by threonine T(668)</scene>, it's an Alzheimer disease-relevant phosphorylation site which is involved in Fe65-binding regulation. The structure together with mutational studies, isothermal titration calorimetry and nuclear magnetic resonance experiments sets the stage for understanding T(668) phosphorylation-dependent complex regulation at a molecular level.<ref>PMID:18833287</ref> Mutation at Thr-668 of APP abolished the effect of Fe65 on APP maturation. This mutation blocked the Fe65-dependent suppression of Abeta production and resulted in the release of increased levels of Abeta in the presence of Fe65 <ref>PMID:11517218</ref> . | ||
== Functions of human APP and Fe65 protein == | == Functions of human APP and Fe65 protein == | ||
There are suggestions that the binding of APP with Fe65 has been implicated in regulating cell motility and growth cone dynamics <ref>PMID: 11425871</ref> <ref>PMID: 12843239</ref> | There are suggestions that the binding of APP with Fe65 has been implicated in regulating cell motility and growth cone dynamics <ref>PMID:11425871</ref> <ref>PMID:12843239</ref> | ||
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>PMID: 19225519</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> | ||
