Human APP Intracellular Domain Complex with Fe65-PTB2: Difference between revisions
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<scene name='SANDBOX138/Chains_bandd/1'>Chains B et D are also identical</scene>. Each contains 35 residues: 2 helices and 1 strand. They represent APP intracellular doamin. | <scene name='SANDBOX138/Chains_bandd/1'>Chains B et D are also identical</scene>. Each contains 35 residues: 2 helices and 1 strand. They represent APP intracellular doamin. | ||
The crystal structure of the APP intracellular domain is in complex with the C-terminal phosphotyrosine-binding (PTB) domain of Fe65. 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 capped by threonine T(668), 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>2</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>3</ref> | The crystal structure of the APP intracellular domain is in complex with the C-terminal phosphotyrosine-binding (PTB) domain of Fe65. 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 capped by threonine T(668), 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>2</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>3</ref> | ||
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The question of normal biological function of APP in neurons, in which it is predominantly located at synapses, is still unclear. <ref>5</ref> Anyway, there are suggestions that the binding of APP with Fe65 has been implicated in regulating cell motility and growth cone dynamics <ref>6</ref> <ref>7</ref> | The question of normal biological function of APP in neurons, in which it is predominantly located at synapses, is still unclear. <ref>5</ref> Anyway, there are suggestions that the binding of APP with Fe65 has been implicated in regulating cell motility and growth cone dynamics <ref>6</ref> <ref>7</ref> | ||
There are at present several potential mechanisms whereby APP may contribute to neurotoxicity: via γ-secretase cleavage to release AICD or via alternative cleavage of the APP C-terminus to release other cytotoxic peptides.<ref>8</ref> | There are at present several potential mechanisms whereby APP may contribute to neurotoxicity: via γ-secretase cleavage to release AICD or via alternative cleavage of the APP C-terminus to release other cytotoxic peptides.<ref>8</ref> | ||
Fe65 is an adaptor protein localized in the nucleus. It interacts with the Alzheimer's disease amyloid precursor protein (APP), transcription factor CP2/LSF/LBP1 and the low-density lipoprotein receptor-related protein. APP functions as a cytosolic anchoring site that can prevent the gene product's nuclear translocation. This encoded protein could play an important role in the pathogenesis of Alzheimer's disease. It is thought to regulate transcription. Also it is observed to block cell cycle progression by downregulating thymidylate synthase expression. Multiple alternatively spliced transcript variants have been described for this gene but some of their full length sequence is not known.[provided by RefSeq].refer 9 | |||
Fe65 plays a central role in the response to DNA damage by translocating to the nucleus and inducing apoptosis. May act by specifically recognizing and binding histone H2AX phosphorylated on 'Tyr-142' (H2AXY142ph) at double-strand breaks (DSBs), recruiting other pro-apoptosis factors such as MAPK8/JNK1.Required for histone H4 acetylation at double-strand breaks (DSBs).Its ability to specifically bind modified histones and chromatin modifying enzymes such as KAT5/TIP60, probably explains its trancription activation activity.http://www.ncbi.nlm.nih.gov/protein/Q9QXJ1.2?ordinalpos=6&itool=EntrezSystem2.PEntrez.Sequence.Sequence_ResultsPanel.Sequence_RVDocSum | |||
== APP and Alzheimer disease == | == APP and Alzheimer disease == | ||
