Human APP Intracellular Domain Complex with Fe65-PTB2: Difference between revisions
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{{STRUCTURE_3dxc | PDB=3dxc | SIZE=400| SCENE= |right| CAPTION=Human amyloid precursor protein residues 739-770 complex with Fe65-PTB2, [[3dxc]] }}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 implicated in production of Abeta and in signalling in APP. | |||
== Structure == | == Structure == | ||
This crystal 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/2'>Chains B and D are also identical</scene>. Each contains 35 residues: 2 helices and 1 strand. They represent APP intracellular domain. | |||
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 | |||
<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> . | ||
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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 | 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. 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.<ref>[http://www.ncbi.nlm.nih.gov/protein/NP_001155.1?ordinalpos=1&itool=EntrezSystem2.PEntrez.Sequence.Sequence_ResultsPanel.Sequence_RVDocSum NCBI Reference Sequence: NP_001155.1]</ref> | ||
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 | 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 transcription activation activity. <ref>[http://www.uniprot.org/uniprot/O00213 UniProtKB/Swiss-Prot O00213 (APBB1_HUMAN)]</ref> | ||
== Location == | == Location == | ||
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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)<ref>PMID: | In the 2006, there were 22.6 million people affected with Alzheimer disease, estimations predict by the year 2050 up to 106.8 cases worldwide. <ref>PMID: 19595937</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)<ref>Vivian Hook, Israel Schechter, Hans-Ulrich Demuth, Gregory Hook. Alternative Pathways for Production of Beta-Amyloid Peptides of Alzheimer's Disease.Biol Chem. 2008 August; 389(8): 993-1006. [http://www.ncbi.nlm.nih.gov:80/pmc/articles/PMC2654319/?tool=pmcentrez PMCID: PMC2654319]</ref> | |||
There is an association between Aβ protein and Alzheimer’s disease because it is the major component found in plaques that are found in Alzheimer patients. Increased levels of Aβ protein are linked to a decrease of cognitive abilities which are observed in Alzheimer patients. <ref>PMID: 19374683</ref> | |||
Besides neuritic plaques neurofibrillary tangles containing hyperphosphorylated tau protein are characteristic in the neuropathology of Alzheimer’s disease. Hyperphosphorylated tau protein and accumulated Aβ protein are considered to coexist. <ref>PMID: 19158417</ref> | |||
==3D structures of amyloid precursor protein== | |||
[[Amyloid precursor protein]] | |||
===Additional Resources=== | |||
For additional information, see: [[Alzheimer's Disease]] | |||
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== References == | == References == | ||
