Proteopedia - User contributions [en]

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-11-19T21:55:18Z

Alexandra Balueva: /* Functions of human APP and Fe65 protein */

'''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 implicated in production of Abeta and in signalling in APP.
{{STRUCTURE_3dxc | PDB=3dxc | SCENE= }}

== 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
<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 ==

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.

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>PMID:9168929</ref> <ref>PMID:11544248</ref> <ref>PMID:11943163</ref> <ref>PMID:19225519</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. 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 transcription activation activity. <ref>[http://www.uniprot.org/uniprot/O00213 UniProtKB/Swiss-Prot O00213 (APBB1_HUMAN)]</ref>

== Location ==
Fe65 could be located in cell membrane, cytoplasm, nucleus. In normal conditions, it mainly localizes to the cytoplasm, while a
small fraction is tethered to the cell membrane via its interaction with APP. Following exposure to DNA damaging agents, it is released
from cell membrane and translocates to the nucleus. Nuclear translocation is under the regulation of APP.<ref>[http://www.uniprot.org/uniprot/O00213 UniProtKB/Swiss-Prot O00213 (APBB1_HUMAN)]</ref>

APP is a cell surface protein that rapidly becomes internalized via clathrin-coated pits. During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated). After alpha-secretase cleavage, soluble APP is released into the extracellular space and the C-terminal is internalized to endosomes and lysosomes. Some APP accumulates in secretory transport vesicles leaving the late Golgi compartment and returns to the cell surface. Gamma-[]CTF(59) peptide is located to both the cytoplasm and nuclei of neurons. It can be translocated to the nucleus through association with APBB1 (Fe65). Beta-APP42 associates with FRPL1 at the cell surface and the complex is then rapidly internalized. APP sorts to the basolateral surface in epithelial cells. During neuronal differentiation, the Thr-743 phosphorylated form is located mainly in growth cones, moderately in neurites and sparingly in the cell body. Casein kinase phosphorylation can occur either at the cell surface or within a post-Golgi compartment <ref>PMID:11544248</ref>

== APP and Alzheimer disease ==
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>

== References ==
<references />

== Further reading ==

[http://www.alzheimer.ca/english/index.php Alzheimer Society of Canada]

[http://www.alzforum.org/ Alzforum: Alzheimer Research Forum]

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-11-19T21:52:23Z

Alexandra Balueva: /* Functions of human APP and Fe65 protein */

'''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 implicated in production of Abeta and in signalling in APP.
{{STRUCTURE_3dxc | PDB=3dxc | SCENE= }}

== 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
<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 ==

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.

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>PMID:9168929</ref> <ref>PMID:11544248</ref> <ref>PMID:11943163</ref> <ref>PMID:19225519</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. 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 trancription activation activity. <ref>[http://www.uniprot.org/uniprot/O00213 UniProtKB/Swiss-Prot O00213 (APBB1_HUMAN)]</ref>

== Location ==
Fe65 could be located in cell membrane, cytoplasm, nucleus. In normal conditions, it mainly localizes to the cytoplasm, while a
small fraction is tethered to the cell membrane via its interaction with APP. Following exposure to DNA damaging agents, it is released
from cell membrane and translocates to the nucleus. Nuclear translocation is under the regulation of APP.<ref>[http://www.uniprot.org/uniprot/O00213 UniProtKB/Swiss-Prot O00213 (APBB1_HUMAN)]</ref>

APP is a cell surface protein that rapidly becomes internalized via clathrin-coated pits. During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated). After alpha-secretase cleavage, soluble APP is released into the extracellular space and the C-terminal is internalized to endosomes and lysosomes. Some APP accumulates in secretory transport vesicles leaving the late Golgi compartment and returns to the cell surface. Gamma-[]CTF(59) peptide is located to both the cytoplasm and nuclei of neurons. It can be translocated to the nucleus through association with APBB1 (Fe65). Beta-APP42 associates with FRPL1 at the cell surface and the complex is then rapidly internalized. APP sorts to the basolateral surface in epithelial cells. During neuronal differentiation, the Thr-743 phosphorylated form is located mainly in growth cones, moderately in neurites and sparingly in the cell body. Casein kinase phosphorylation can occur either at the cell surface or within a post-Golgi compartment <ref>PMID:11544248</ref>

== APP and Alzheimer disease ==
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>

== References ==
<references />

== Further reading ==

[http://www.alzheimer.ca/english/index.php Alzheimer Society of Canada]

[http://www.alzforum.org/ Alzforum: Alzheimer Research Forum]

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-11-19T12:26:41Z

Alexandra Balueva: /* APP and Alzheimer disease */

'''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 implicated in production of Abeta and in signalling in APP.
{{STRUCTURE_3dxc | PDB=3dxc | SCENE= }}

== 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
<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 ==

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.

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>PMID:9168929</ref> <ref>PMID:11544248</ref> <ref>PMID:11943163</ref> <ref>PMID:19225519</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.<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 trancription activation activity. <ref>[http://www.uniprot.org/uniprot/O00213 UniProtKB/Swiss-Prot O00213 (APBB1_HUMAN)]</ref>

== Location ==
Fe65 could be located in cell membrane, cytoplasm, nucleus. In normal conditions, it mainly localizes to the cytoplasm, while a
small fraction is tethered to the cell membrane via its interaction with APP. Following exposure to DNA damaging agents, it is released
from cell membrane and translocates to the nucleus. Nuclear translocation is under the regulation of APP.<ref>[http://www.uniprot.org/uniprot/O00213 UniProtKB/Swiss-Prot O00213 (APBB1_HUMAN)]</ref>

APP is a cell surface protein that rapidly becomes internalized via clathrin-coated pits. During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated). After alpha-secretase cleavage, soluble APP is released into the extracellular space and the C-terminal is internalized to endosomes and lysosomes. Some APP accumulates in secretory transport vesicles leaving the late Golgi compartment and returns to the cell surface. Gamma-[]CTF(59) peptide is located to both the cytoplasm and nuclei of neurons. It can be translocated to the nucleus through association with APBB1 (Fe65). Beta-APP42 associates with FRPL1 at the cell surface and the complex is then rapidly internalized. APP sorts to the basolateral surface in epithelial cells. During neuronal differentiation, the Thr-743 phosphorylated form is located mainly in growth cones, moderately in neurites and sparingly in the cell body. Casein kinase phosphorylation can occur either at the cell surface or within a post-Golgi compartment <ref>PMID:11544248</ref>

== APP and Alzheimer disease ==
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>

== References ==
<references />

== Further reading ==

[http://www.alzheimer.ca/english/index.php Alzheimer Society of Canada]

[http://www.alzforum.org/ Alzforum: Alzheimer Research Forum]

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-11-19T12:24:14Z

Alexandra Balueva:

'''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 implicated in production of Abeta and in signalling in APP.
{{STRUCTURE_3dxc | PDB=3dxc | SCENE= }}

== 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
<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 ==

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.

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>PMID:9168929</ref> <ref>PMID:11544248</ref> <ref>PMID:11943163</ref> <ref>PMID:19225519</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.<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 trancription activation activity. <ref>[http://www.uniprot.org/uniprot/O00213 UniProtKB/Swiss-Prot O00213 (APBB1_HUMAN)]</ref>

== Location ==
Fe65 could be located in cell membrane, cytoplasm, nucleus. In normal conditions, it mainly localizes to the cytoplasm, while a
small fraction is tethered to the cell membrane via its interaction with APP. Following exposure to DNA damaging agents, it is released
from cell membrane and translocates to the nucleus. Nuclear translocation is under the regulation of APP.<ref>[http://www.uniprot.org/uniprot/O00213 UniProtKB/Swiss-Prot O00213 (APBB1_HUMAN)]</ref>

APP is a cell surface protein that rapidly becomes internalized via clathrin-coated pits. During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated). After alpha-secretase cleavage, soluble APP is released into the extracellular space and the C-terminal is internalized to endosomes and lysosomes. Some APP accumulates in secretory transport vesicles leaving the late Golgi compartment and returns to the cell surface. Gamma-[]CTF(59) peptide is located to both the cytoplasm and nuclei of neurons. It can be translocated to the nucleus through association with APBB1 (Fe65). Beta-APP42 associates with FRPL1 at the cell surface and the complex is then rapidly internalized. APP sorts to the basolateral surface in epithelial cells. During neuronal differentiation, the Thr-743 phosphorylated form is located mainly in growth cones, moderately in neurites and sparingly in the cell body. Casein kinase phosphorylation can occur either at the cell surface or within a post-Golgi compartment <ref>PMID:11544248</ref>

== APP and Alzheimer disease ==
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>
== References ==
<references />

== Further reading ==

[http://www.alzheimer.ca/english/index.php Alzheimer Society of Canada]

[http://www.alzforum.org/ Alzforum: Alzheimer Research Forum]

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-11-19T12:21:04Z

Alexandra Balueva: /* APP and Alzheimer disease */

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-11-01T19:32:01Z

Alexandra Balueva:

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-11-01T19:08:55Z

Alexandra Balueva:

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-11-01T18:29:45Z

Alexandra Balueva: /* Structure */

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-11-01T18:29:20Z

Alexandra Balueva: /* Structure */

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-11-01T18:27:51Z

Alexandra Balueva: /* Functions of human APP and Fe65 protein */

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-11-01T18:12:44Z

Alexandra Balueva: /* APP and Alzheimer disease */

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-11-01T18:11:09Z

Alexandra Balueva: /* Location */

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-11-01T18:06:21Z

Alexandra Balueva:

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-11-01T18:02:57Z

Alexandra Balueva:

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-11-01T18:00:15Z

Alexandra Balueva:

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-11-01T17:59:01Z

Alexandra Balueva:

'''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.
{{STRUCTURE_3dxc | PDB=3dxc | SCENE= }}

== Structure ==

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 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
<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 ==

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.

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>PMID:9168929</ref> <ref>PMID:11544248</ref> <ref>PMID:11943163</ref> <ref>PMID:19225519</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].<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 trancription activation activity. <ref>[http://www.uniprot.org/uniprot/O00213 UniProtKB/Swiss-Prot O00213 (APBB1_HUMAN)]</ref>

== Location ==
Fe65 could be located in cell membrane, cytoplasm, nucleus. In normal conditions, it mainly localizes to the cytoplasm, while a
small fraction is tethered to the cell membrane via its interaction with APP. Following exposure to DNA damaging agents, it is released
from cell membrane and translocates to the nucleus. Nuclear translocation is under the regulation of APP.<ref>[http://www.uniprot.org/uniprot/O00213 UniProtKB/Swiss-Prot O00213 (APBB1_HUMAN)]</ref>

Cell surface protein that rapidly becomes internalized via clathrin-coated pits. During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated). After alpha-secretase cleavage, soluble APP is released into the extracellular space and the C-terminal is internalized to endosomes and lysosomes. Some APP accumulates in secretory transport vesicles leaving the late Golgi compartment and returns to the cell surface. Gamma-CTF(59) peptide is located to both the cytoplasm and nuclei of neurons. It can be translocated to the nucleus through association with APBB1 (Fe65). Beta-APP42 associates with FRPL1 at the cell surface and the complex is then rapidly internalized. APP sorts to the basolateral surface in epithelial cells. During neuronal differentiation, the Thr-743 phosphorylated form is located mainly in growth cones, moderately in neurites and sparingly in the cell body. Casein kinase phosphorylation can occur either at the cell surface or within a post-Golgi compartment <ref>13</ref>

== 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>PMID:2654319</ref>

== References ==
<references />

10. [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]

11. http://www.ncbi.nlm.nih.gov/protein/Q9QXJ1.2?ordinalpos=6&itool=EntrezSystem2.PEntrez.Sequence.Sequence_ResultsPanel.Sequence_RVDocSum

12. http://www.ncbi.nlm.nih.gov/protein/Q9QXJ1.2?ordinalpos=6&itool=EntrezSystem2.PEntrez.Sequence.Sequence_ResultsPanel.Sequence_RVDocSum

13. "The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner."
Kimberly W.T., Zheng J.B., Guenette S.Y., Selkoe D.J.
J. Biol. Chem. 276:40288-40292(2001) [PubMed: 11544248] [Abstract]
Cited for: INTERACTION WITH APBB1, FUNCTION, SUBCELLULAR LOCATION.

14. 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]

== Further reading ==

[http://www.alzheimer.ca/english/index.php Alzheimer Society of Canada]

[http://www.alzheimer-adna.com/ Association pour le Développement des Neurosciences Appliquées]

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-11-01T17:58:16Z

Alexandra Balueva:

'''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.
{{STRUCTURE_3dxc | PDB=3dxc | SCENE= }}

== Structure ==

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 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
<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 ==

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.

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>PMID:9168929</ref> <ref>PMID:11544248</ref> <ref>PMID:11943163</ref> <ref>PMID:19225519</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].<ref>10</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 trancription activation activity. <ref>[http://www.uniprot.org/uniprot/O00213 UniProtKB/Swiss-Prot O00213 (APBB1_HUMAN)]</ref>

== Location ==
Fe65 could be located in cell membrane, cytoplasm, nucleus. In normal conditions, it mainly localizes to the cytoplasm, while a
small fraction is tethered to the cell membrane via its interaction with APP. Following exposure to DNA damaging agents, it is released
from cell membrane and translocates to the nucleus. Nuclear translocation is under the regulation of APP.<ref>[http://www.uniprot.org/uniprot/O00213 UniProtKB/Swiss-Prot O00213 (APBB1_HUMAN)]</ref>

Cell surface protein that rapidly becomes internalized via clathrin-coated pits. During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated). After alpha-secretase cleavage, soluble APP is released into the extracellular space and the C-terminal is internalized to endosomes and lysosomes. Some APP accumulates in secretory transport vesicles leaving the late Golgi compartment and returns to the cell surface. Gamma-CTF(59) peptide is located to both the cytoplasm and nuclei of neurons. It can be translocated to the nucleus through association with APBB1 (Fe65). Beta-APP42 associates with FRPL1 at the cell surface and the complex is then rapidly internalized. APP sorts to the basolateral surface in epithelial cells. During neuronal differentiation, the Thr-743 phosphorylated form is located mainly in growth cones, moderately in neurites and sparingly in the cell body. Casein kinase phosphorylation can occur either at the cell surface or within a post-Golgi compartment <ref>13</ref>

== 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>PMID:2654319</ref>

== References ==
<references />

10. [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]

11. http://www.ncbi.nlm.nih.gov/protein/Q9QXJ1.2?ordinalpos=6&itool=EntrezSystem2.PEntrez.Sequence.Sequence_ResultsPanel.Sequence_RVDocSum

12. http://www.ncbi.nlm.nih.gov/protein/Q9QXJ1.2?ordinalpos=6&itool=EntrezSystem2.PEntrez.Sequence.Sequence_ResultsPanel.Sequence_RVDocSum

13. "The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner."
Kimberly W.T., Zheng J.B., Guenette S.Y., Selkoe D.J.
J. Biol. Chem. 276:40288-40292(2001) [PubMed: 11544248] [Abstract]
Cited for: INTERACTION WITH APBB1, FUNCTION, SUBCELLULAR LOCATION.

14. 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]

== Further reading ==

[http://www.alzheimer.ca/english/index.php Alzheimer Society of Canada]

[http://www.alzheimer-adna.com/ Association pour le Développement des Neurosciences Appliquées]

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-11-01T17:34:38Z

Alexandra Balueva: /* References */

'''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.
{{STRUCTURE_3dxc | PDB=3dxc | SCENE= }}

== Structure ==

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 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
<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 ==

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.

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>PMID:9168929</ref> <ref>PMID:11544248</ref> <ref>PMID:11943163</ref> <ref>PMID:19225519</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].<ref>10</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 trancription activation activity. <ref>11</ref>

== Location ==
Fe65 could be located in cell membrane, cytoplasm, nucleus. In normal conditions, it mainly localizes to the cytoplasm, while a
small fraction is tethered to the cell membrane via its interaction with APP. Following exposure to DNA damaging agents, it is released
from cell membrane and translocates to the nucleus. Nuclear translocation is under the regulation of APP.<ref>12</ref>

Cell surface protein that rapidly becomes internalized via clathrin-coated pits. During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated). After alpha-secretase cleavage, soluble APP is released into the extracellular space and the C-terminal is internalized to endosomes and lysosomes. Some APP accumulates in secretory transport vesicles leaving the late Golgi compartment and returns to the cell surface. Gamma-CTF(59) peptide is located to both the cytoplasm and nuclei of neurons. It can be translocated to the nucleus through association with APBB1 (Fe65). Beta-APP42 associates with FRPL1 at the cell surface and the complex is then rapidly internalized. APP sorts to the basolateral surface in epithelial cells. During neuronal differentiation, the Thr-743 phosphorylated form is located mainly in growth cones, moderately in neurites and sparingly in the cell body. Casein kinase phosphorylation can occur either at the cell surface or within a post-Golgi compartment <ref>13</ref>

== 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>PMID:2654319</ref>

== References ==
<references />

10. [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]

11. http://www.ncbi.nlm.nih.gov/protein/Q9QXJ1.2?ordinalpos=6&itool=EntrezSystem2.PEntrez.Sequence.Sequence_ResultsPanel.Sequence_RVDocSum

12. http://www.ncbi.nlm.nih.gov/protein/Q9QXJ1.2?ordinalpos=6&itool=EntrezSystem2.PEntrez.Sequence.Sequence_ResultsPanel.Sequence_RVDocSum

13. "The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner."
Kimberly W.T., Zheng J.B., Guenette S.Y., Selkoe D.J.
J. Biol. Chem. 276:40288-40292(2001) [PubMed: 11544248] [Abstract]
Cited for: INTERACTION WITH APBB1, FUNCTION, SUBCELLULAR LOCATION.

14. 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]

== Further reading ==

[http://www.alzheimer.ca/english/index.php Alzheimer Society of Canada]

[http://www.alzheimer-adna.com/ Association pour le Développement des Neurosciences Appliquées]

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-11-01T17:33:07Z

Alexandra Balueva: /* References */

'''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.
{{STRUCTURE_3dxc | PDB=3dxc | SCENE= }}

== Structure ==

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 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
<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 ==

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.

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>PMID:9168929</ref> <ref>PMID:11544248</ref> <ref>PMID:11943163</ref> <ref>PMID:19225519</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].<ref>10</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 trancription activation activity. <ref>11</ref>

== Location ==
Fe65 could be located in cell membrane, cytoplasm, nucleus. In normal conditions, it mainly localizes to the cytoplasm, while a
small fraction is tethered to the cell membrane via its interaction with APP. Following exposure to DNA damaging agents, it is released
from cell membrane and translocates to the nucleus. Nuclear translocation is under the regulation of APP.<ref>12</ref>

Cell surface protein that rapidly becomes internalized via clathrin-coated pits. During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated). After alpha-secretase cleavage, soluble APP is released into the extracellular space and the C-terminal is internalized to endosomes and lysosomes. Some APP accumulates in secretory transport vesicles leaving the late Golgi compartment and returns to the cell surface. Gamma-CTF(59) peptide is located to both the cytoplasm and nuclei of neurons. It can be translocated to the nucleus through association with APBB1 (Fe65). Beta-APP42 associates with FRPL1 at the cell surface and the complex is then rapidly internalized. APP sorts to the basolateral surface in epithelial cells. During neuronal differentiation, the Thr-743 phosphorylated form is located mainly in growth cones, moderately in neurites and sparingly in the cell body. Casein kinase phosphorylation can occur either at the cell surface or within a post-Golgi compartment <ref>13</ref>

== 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>PMID:2654319</ref>

== References ==
<references />

2. Radzimanowski J, Simon B, Sattler M, Beyreuther K, Sinning I, Wild K. (2008) Structure of the intracellular domain of the amyloid precursor protein in complex with Fe65-PTB2. ''Embo Rep.'' v9 pp. 1134-40. [http://www.ncbi.nlm.nih.gov/pubmed/18833287?dopt=Abstract PMID 18833287]

3. Ando K, Iijima KI, Elliott JI, Kirino Y, Suzuki T. Phosphorylation-dependent regulation of the interaction of amyloid precursor protein with Fe65 affects the production of beta-amyloid.J Biol Chem. 2001 Oct 26;276(43):40353-61. Epub 2001 Aug 21. [http://www.ncbi.nlm.nih.gov/pubmed/11517218itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=5 PMID: 11517218]

4. Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The Alzheimer amyloid precursor protein (APP) and FE65, an APP-binding protein, regulate cell movement. J Cell Biol. 2001;153:1403-1414. [PubMed Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The Alzheimer amyloid precursor protein (APP) and FE65, an APP-binding protein, regulate cell movement. J Cell Biol. 2001;153:1403-1414. [PubMed PMID: 11425871]

5. Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The amyloid precursor protein and its regulatory protein, FE65, in growth cones and synapses in vitro and in vivo. J Neurosci. 2003;23:5407-5415. [PMID: 12843239]

6. "Alzheimer's disease amyloid beta peptide 25-35 inhibits lipid peroxidation as a result of its membrane interactions."
Walter M.F., Mason P.E., Mason R.P.
Biochem. Biophys. Res. Commun. 233:760-764(1997) [PubMed: 9168929] [Abstract]
Cited for: FUNCTION OF BETA-AMYLOID PEPTIDE AS LIPID PEROXIDATION INHIBITOR, MUTAGENESIS OF MET-706.

7. "The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner."
Kimberly W.T., Zheng J.B., Guenette S.Y., Selkoe D.J.
J. Biol. Chem. 276:40288-40292(2001) [PubMed: 11544248] [Abstract]
Cited for: INTERACTION WITH APBB1, FUNCTION, SUBCELLULAR LOCATION.

8. "Direct interaction of soluble human recombinant tau protein with Abeta 1-42 results in tau aggregation and hyperphosphorylation by tau protein kinase II."
Rank K.B., Pauley A.M., Bhattacharya K., Wang Z., Evans D.B., Fleck T.J., Johnston J.A., Sharma S.K.
FEBS Lett. 514:263-268(2002) [PubMed: 11943163] [Abstract]
Cited for: INTERACTION WITH MAPT, FUNCTION.

9. "APP binds DR6 to trigger axon pruning and neuron death via distinct caspases."
Nikolaev A., McLaughlin T., O'Leary D.D.M., Tessier-Lavigne M.
Nature 457:981-989(2009) [PubMed: 19225519] [Abstract]
Cited for: FUNCTION, CLEAVAGE, INTERACTION WITH TNFRSF21.

10. [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]

11. http://www.ncbi.nlm.nih.gov/protein/Q9QXJ1.2?ordinalpos=6&itool=EntrezSystem2.PEntrez.Sequence.Sequence_ResultsPanel.Sequence_RVDocSum

12. http://www.ncbi.nlm.nih.gov/protein/Q9QXJ1.2?ordinalpos=6&itool=EntrezSystem2.PEntrez.Sequence.Sequence_ResultsPanel.Sequence_RVDocSum

13. "The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner."
Kimberly W.T., Zheng J.B., Guenette S.Y., Selkoe D.J.
J. Biol. Chem. 276:40288-40292(2001) [PubMed: 11544248] [Abstract]
Cited for: INTERACTION WITH APBB1, FUNCTION, SUBCELLULAR LOCATION.

14. 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]

== Further reading ==

[http://www.alzheimer.ca/english/index.php Alzheimer Society of Canada]

[http://www.alzheimer-adna.com/ Association pour le Développement des Neurosciences Appliquées]

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-11-01T17:30:08Z

Alexandra Balueva:

'''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.
{{STRUCTURE_3dxc | PDB=3dxc | SCENE= }}

== Structure ==

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 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
<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 ==

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.

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>PMID:9168929</ref> <ref>PMID:11544248</ref> <ref>PMID:11943163</ref> <ref>PMID:19225519</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].<ref>10</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 trancription activation activity. <ref>11</ref>

== Location ==
Fe65 could be located in cell membrane, cytoplasm, nucleus. In normal conditions, it mainly localizes to the cytoplasm, while a
small fraction is tethered to the cell membrane via its interaction with APP. Following exposure to DNA damaging agents, it is released
from cell membrane and translocates to the nucleus. Nuclear translocation is under the regulation of APP.<ref>12</ref>

Cell surface protein that rapidly becomes internalized via clathrin-coated pits. During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated). After alpha-secretase cleavage, soluble APP is released into the extracellular space and the C-terminal is internalized to endosomes and lysosomes. Some APP accumulates in secretory transport vesicles leaving the late Golgi compartment and returns to the cell surface. Gamma-CTF(59) peptide is located to both the cytoplasm and nuclei of neurons. It can be translocated to the nucleus through association with APBB1 (Fe65). Beta-APP42 associates with FRPL1 at the cell surface and the complex is then rapidly internalized. APP sorts to the basolateral surface in epithelial cells. During neuronal differentiation, the Thr-743 phosphorylated form is located mainly in growth cones, moderately in neurites and sparingly in the cell body. Casein kinase phosphorylation can occur either at the cell surface or within a post-Golgi compartment <ref>13</ref>

== 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>PMID:2654319</ref>

== References ==
<references />

1. Radzimanowski J, Simon B, Sattler M, Beyreuther K, Sinning I, Wild K. (2008) Structure of the intracellular domain of the amyloid precursor protein in complex with Fe65-PTB2. ''Embo Rep.'' v9 pp. 1134-40. [http://www.ncbi.nlm.nih.gov/pubmed/18833287?dopt=Abstract PMID 18833287]

2. Radzimanowski J, Simon B, Sattler M, Beyreuther K, Sinning I, Wild K. (2008) Structure of the intracellular domain of the amyloid precursor protein in complex with Fe65-PTB2. ''Embo Rep.'' v9 pp. 1134-40. [http://www.ncbi.nlm.nih.gov/pubmed/18833287?dopt=Abstract PMID 18833287]

3. Ando K, Iijima KI, Elliott JI, Kirino Y, Suzuki T. Phosphorylation-dependent regulation of the interaction of amyloid precursor protein with Fe65 affects the production of beta-amyloid.J Biol Chem. 2001 Oct 26;276(43):40353-61. Epub 2001 Aug 21. [http://www.ncbi.nlm.nih.gov/pubmed/11517218itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=5 PMID: 11517218]

4. Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The Alzheimer amyloid precursor protein (APP) and FE65, an APP-binding protein, regulate cell movement. J Cell Biol. 2001;153:1403-1414. [PubMed Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The Alzheimer amyloid precursor protein (APP) and FE65, an APP-binding protein, regulate cell movement. J Cell Biol. 2001;153:1403-1414. [PubMed PMID: 11425871]

5. Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The amyloid precursor protein and its regulatory protein, FE65, in growth cones and synapses in vitro and in vivo. J Neurosci. 2003;23:5407-5415. [PMID: 12843239]

6. "Alzheimer's disease amyloid beta peptide 25-35 inhibits lipid peroxidation as a result of its membrane interactions."
Walter M.F., Mason P.E., Mason R.P.
Biochem. Biophys. Res. Commun. 233:760-764(1997) [PubMed: 9168929] [Abstract]
Cited for: FUNCTION OF BETA-AMYLOID PEPTIDE AS LIPID PEROXIDATION INHIBITOR, MUTAGENESIS OF MET-706.

7. "The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner."
Kimberly W.T., Zheng J.B., Guenette S.Y., Selkoe D.J.
J. Biol. Chem. 276:40288-40292(2001) [PubMed: 11544248] [Abstract]
Cited for: INTERACTION WITH APBB1, FUNCTION, SUBCELLULAR LOCATION.

8. "Direct interaction of soluble human recombinant tau protein with Abeta 1-42 results in tau aggregation and hyperphosphorylation by tau protein kinase II."
Rank K.B., Pauley A.M., Bhattacharya K., Wang Z., Evans D.B., Fleck T.J., Johnston J.A., Sharma S.K.
FEBS Lett. 514:263-268(2002) [PubMed: 11943163] [Abstract]
Cited for: INTERACTION WITH MAPT, FUNCTION.

9. "APP binds DR6 to trigger axon pruning and neuron death via distinct caspases."
Nikolaev A., McLaughlin T., O'Leary D.D.M., Tessier-Lavigne M.
Nature 457:981-989(2009) [PubMed: 19225519] [Abstract]
Cited for: FUNCTION, CLEAVAGE, INTERACTION WITH TNFRSF21.

10. [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]

11. http://www.ncbi.nlm.nih.gov/protein/Q9QXJ1.2?ordinalpos=6&itool=EntrezSystem2.PEntrez.Sequence.Sequence_ResultsPanel.Sequence_RVDocSum

12. http://www.ncbi.nlm.nih.gov/protein/Q9QXJ1.2?ordinalpos=6&itool=EntrezSystem2.PEntrez.Sequence.Sequence_ResultsPanel.Sequence_RVDocSum

13. "The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner."
Kimberly W.T., Zheng J.B., Guenette S.Y., Selkoe D.J.
J. Biol. Chem. 276:40288-40292(2001) [PubMed: 11544248] [Abstract]
Cited for: INTERACTION WITH APBB1, FUNCTION, SUBCELLULAR LOCATION.

14. 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]

== Further reading ==

[http://www.alzheimer.ca/english/index.php Alzheimer Society of Canada]

[http://www.alzheimer-adna.com/ Association pour le Développement des Neurosciences Appliquées]

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-11-01T15:33:36Z

Alexandra Balueva:

'''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.
{{STRUCTURE_3dxc | PDB=3dxc | SCENE= }}

== Structure ==

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 et 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
<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 ==

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.

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>PubMed: 19225519</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].<ref>10</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 trancription activation activity. <ref>11</ref>

== Location ==
Fe65 could be located in cell membrane, cytoplasm, nucleus. In normal conditions, it mainly localizes to the cytoplasm, while a
small fraction is tethered to the cell membrane via its interaction with APP. Following exposure to DNA damaging agents, it is released
from cell membrane and translocates to the nucleus. Nuclear translocation is under the regulation of APP.<ref>12</ref>

Cell surface protein that rapidly becomes internalized via clathrin-coated pits. During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated). After alpha-secretase cleavage, soluble APP is released into the extracellular space and the C-terminal is internalized to endosomes and lysosomes. Some APP accumulates in secretory transport vesicles leaving the late Golgi compartment and returns to the cell surface. Gamma-CTF(59) peptide is located to both the cytoplasm and nuclei of neurons. It can be translocated to the nucleus through association with APBB1 (Fe65). Beta-APP42 associates with FRPL1 at the cell surface and the complex is then rapidly internalized. APP sorts to the basolateral surface in epithelial cells. During neuronal differentiation, the Thr-743 phosphorylated form is located mainly in growth cones, moderately in neurites and sparingly in the cell body. Casein kinase phosphorylation can occur either at the cell surface or within a post-Golgi compartment <ref>13</ref>

== 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>PMCID: PMC2654319</ref>

== References ==
<references />

1. Radzimanowski J, Simon B, Sattler M, Beyreuther K, Sinning I, Wild K. (2008) Structure of the intracellular domain of the amyloid precursor protein in complex with Fe65-PTB2. ''Embo Rep.'' v9 pp. 1134-40. [http://www.ncbi.nlm.nih.gov/pubmed/18833287?dopt=Abstract PMID 18833287]

2. Radzimanowski J, Simon B, Sattler M, Beyreuther K, Sinning I, Wild K. (2008) Structure of the intracellular domain of the amyloid precursor protein in complex with Fe65-PTB2. ''Embo Rep.'' v9 pp. 1134-40. [http://www.ncbi.nlm.nih.gov/pubmed/18833287?dopt=Abstract PMID 18833287]

3. Ando K, Iijima KI, Elliott JI, Kirino Y, Suzuki T. Phosphorylation-dependent regulation of the interaction of amyloid precursor protein with Fe65 affects the production of beta-amyloid.J Biol Chem. 2001 Oct 26;276(43):40353-61. Epub 2001 Aug 21. [http://www.ncbi.nlm.nih.gov/pubmed/11517218itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=5 PMID: 11517218]

4. Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The Alzheimer amyloid precursor protein (APP) and FE65, an APP-binding protein, regulate cell movement. J Cell Biol. 2001;153:1403-1414. [PubMed Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The Alzheimer amyloid precursor protein (APP) and FE65, an APP-binding protein, regulate cell movement. J Cell Biol. 2001;153:1403-1414. [PubMed PMID: 11425871

5. Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The amyloid precursor protein and its regulatory protein, FE65, in growth cones and synapses in vitro and in vivo. J Neurosci. 2003;23:5407-5415. [PMID: 12843239

6. "Alzheimer's disease amyloid beta peptide 25-35 inhibits lipid peroxidation as a result of its membrane interactions."
Walter M.F., Mason P.E., Mason R.P.
Biochem. Biophys. Res. Commun. 233:760-764(1997) [PubMed: 9168929] [Abstract]
Cited for: FUNCTION OF BETA-AMYLOID PEPTIDE AS LIPID PEROXIDATION INHIBITOR, MUTAGENESIS OF MET-706.

7. "The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner."
Kimberly W.T., Zheng J.B., Guenette S.Y., Selkoe D.J.
J. Biol. Chem. 276:40288-40292(2001) [PubMed: 11544248] [Abstract]
Cited for: INTERACTION WITH APBB1, FUNCTION, SUBCELLULAR LOCATION.

8. "Direct interaction of soluble human recombinant tau protein with Abeta 1-42 results in tau aggregation and hyperphosphorylation by tau protein kinase II."
Rank K.B., Pauley A.M., Bhattacharya K., Wang Z., Evans D.B., Fleck T.J., Johnston J.A., Sharma S.K.
FEBS Lett. 514:263-268(2002) [PubMed: 11943163] [Abstract]
Cited for: INTERACTION WITH MAPT, FUNCTION.

9. "APP binds DR6 to trigger axon pruning and neuron death via distinct caspases."
Nikolaev A., McLaughlin T., O'Leary D.D.M., Tessier-Lavigne M.
Nature 457:981-989(2009) [PubMed: 19225519] [Abstract]
Cited for: FUNCTION, CLEAVAGE, INTERACTION WITH TNFRSF21.

10. [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]

11. http://www.ncbi.nlm.nih.gov/protein/Q9QXJ1.2?ordinalpos=6&itool=EntrezSystem2.PEntrez.Sequence.Sequence_ResultsPanel.Sequence_RVDocSum

12. http://www.ncbi.nlm.nih.gov/protein/Q9QXJ1.2?ordinalpos=6&itool=EntrezSystem2.PEntrez.Sequence.Sequence_ResultsPanel.Sequence_RVDocSum

13. "The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner."
Kimberly W.T., Zheng J.B., Guenette S.Y., Selkoe D.J.
J. Biol. Chem. 276:40288-40292(2001) [PubMed: 11544248] [Abstract]
Cited for: INTERACTION WITH APBB1, FUNCTION, SUBCELLULAR LOCATION.

14. 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]

== Further reading ==

[http://www.alzheimer.ca/english/index.php Alzheimer Society of Canada]

[http://www.alzheimer-adna.com/ Association pour le Développement des Neurosciences Appliquées]

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-11-01T15:26:16Z

Alexandra Balueva:

'''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>1</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 ==

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 et 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
<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>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> .

== 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>5</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.

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>9</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].<ref>10</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 trancription activation activity. <ref>11</ref>

== Location ==
Fe65 could be located in cell membrane, cytoplasm, nucleus. In normal conditions, it mainly localizes to the cytoplasm, while a
small fraction is tethered to the cell membrane via its interaction with APP. Following exposure to DNA damaging agents, it is released
from cell membrane and translocates to the nucleus. Nuclear translocation is under the regulation of APP.<ref>12</ref>

Cell surface protein that rapidly becomes internalized via clathrin-coated pits. During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated). After alpha-secretase cleavage, soluble APP is released into the extracellular space and the C-terminal is internalized to endosomes and lysosomes. Some APP accumulates in secretory transport vesicles leaving the late Golgi compartment and returns to the cell surface. Gamma-CTF(59) peptide is located to both the cytoplasm and nuclei of neurons. It can be translocated to the nucleus through association with APBB1 (Fe65). Beta-APP42 associates with FRPL1 at the cell surface and the complex is then rapidly internalized. APP sorts to the basolateral surface in epithelial cells. During neuronal differentiation, the Thr-743 phosphorylated form is located mainly in growth cones, moderately in neurites and sparingly in the cell body. Casein kinase phosphorylation can occur either at the cell surface or within a post-Golgi compartment <ref>13</ref>

== 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>PMCID: PMC2654319</ref>

== References ==
<references />

1. Radzimanowski J, Simon B, Sattler M, Beyreuther K, Sinning I, Wild K. (2008) Structure of the intracellular domain of the amyloid precursor protein in complex with Fe65-PTB2. ''Embo Rep.'' v9 pp. 1134-40. [http://www.ncbi.nlm.nih.gov/pubmed/18833287?dopt=Abstract PMID 18833287]

2. Radzimanowski J, Simon B, Sattler M, Beyreuther K, Sinning I, Wild K. (2008) Structure of the intracellular domain of the amyloid precursor protein in complex with Fe65-PTB2. ''Embo Rep.'' v9 pp. 1134-40. [http://www.ncbi.nlm.nih.gov/pubmed/18833287?dopt=Abstract PMID 18833287]

3. Ando K, Iijima KI, Elliott JI, Kirino Y, Suzuki T. Phosphorylation-dependent regulation of the interaction of amyloid precursor protein with Fe65 affects the production of beta-amyloid.J Biol Chem. 2001 Oct 26;276(43):40353-61. Epub 2001 Aug 21. [http://www.ncbi.nlm.nih.gov/pubmed/11517218itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=5 PMID: 11517218]

4. Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The Alzheimer amyloid precursor protein (APP) and FE65, an APP-binding protein, regulate cell movement. J Cell Biol. 2001;153:1403-1414. [PubMed Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The Alzheimer amyloid precursor protein (APP) and FE65, an APP-binding protein, regulate cell movement. J Cell Biol. 2001;153:1403-1414. [PubMed PMID: 11425871

5. Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The amyloid precursor protein and its regulatory protein, FE65, in growth cones and synapses in vitro and in vivo. J Neurosci. 2003;23:5407-5415. [PubMed] 12843239

6. "Alzheimer's disease amyloid beta peptide 25-35 inhibits lipid peroxidation as a result of its membrane interactions."
Walter M.F., Mason P.E., Mason R.P.
Biochem. Biophys. Res. Commun. 233:760-764(1997) [PubMed: 9168929] [Abstract]
Cited for: FUNCTION OF BETA-AMYLOID PEPTIDE AS LIPID PEROXIDATION INHIBITOR, MUTAGENESIS OF MET-706.

7. "The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner."
Kimberly W.T., Zheng J.B., Guenette S.Y., Selkoe D.J.
J. Biol. Chem. 276:40288-40292(2001) [PubMed: 11544248] [Abstract]
Cited for: INTERACTION WITH APBB1, FUNCTION, SUBCELLULAR LOCATION.

8. "Direct interaction of soluble human recombinant tau protein with Abeta 1-42 results in tau aggregation and hyperphosphorylation by tau protein kinase II."
Rank K.B., Pauley A.M., Bhattacharya K., Wang Z., Evans D.B., Fleck T.J., Johnston J.A., Sharma S.K.
FEBS Lett. 514:263-268(2002) [PubMed: 11943163] [Abstract]
Cited for: INTERACTION WITH MAPT, FUNCTION.

9. "APP binds DR6 to trigger axon pruning and neuron death via distinct caspases."
Nikolaev A., McLaughlin T., O'Leary D.D.M., Tessier-Lavigne M.
Nature 457:981-989(2009) [PubMed: 19225519] [Abstract]
Cited for: FUNCTION, CLEAVAGE, INTERACTION WITH TNFRSF21.

10. [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]

11. http://www.ncbi.nlm.nih.gov/protein/Q9QXJ1.2?ordinalpos=6&itool=EntrezSystem2.PEntrez.Sequence.Sequence_ResultsPanel.Sequence_RVDocSum

12. http://www.ncbi.nlm.nih.gov/protein/Q9QXJ1.2?ordinalpos=6&itool=EntrezSystem2.PEntrez.Sequence.Sequence_ResultsPanel.Sequence_RVDocSum

13. "The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner."
Kimberly W.T., Zheng J.B., Guenette S.Y., Selkoe D.J.
J. Biol. Chem. 276:40288-40292(2001) [PubMed: 11544248] [Abstract]
Cited for: INTERACTION WITH APBB1, FUNCTION, SUBCELLULAR LOCATION.

14. 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]

== Further reading ==

[http://www.alzheimer.ca/english/index.php Alzheimer Society of Canada]

[http://www.alzheimer-adna.com/ Association pour le Développement des Neurosciences Appliquées]

Human APP

2009-10-31T19:53:42Z

Alexandra Balueva: New page: ==This is a placeholder== This is a placeholder text to help you get started in placing a Jmol applet on your page. At any time, click "Show Preview" at the bottom of this page to see how...

==This is a placeholder==
This is a placeholder text to help you get started in
placing a Jmol applet on your page. At any time, click
"Show Preview" at the bottom of this page to see how it goes.

Replace the PDB id (use lowercase!) after the STRUCTURE_ and after PDB= to load
and display another structure.

{{STRUCTURE_3cin | PDB=3cin | SCENE= }}
== 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>4</ref> <ref>5</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.

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>9</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].<ref>10</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 trancription activation activity. <ref>11</ref>

== Location ==
Fe65 could be located in cell membrane, cytoplasm, nucleus. In normal conditions, it mainly localizes to the cytoplasm, while a
small fraction is tethered to the cell membrane via its interaction with APP. Following exposure to DNA damaging agents, it is released
from cell membrane and translocates to the nucleus. Nuclear translocation is under the regulation of APP.<ref>12</ref>

Cell surface protein that rapidly becomes internalized via clathrin-coated pits. During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated). After alpha-secretase cleavage, soluble APP is released into the extracellular space and the C-terminal is internalized to endosomes and lysosomes. Some APP accumulates in secretory transport vesicles leaving the late Golgi compartment and returns to the cell surface. Gamma-CTF(59) peptide is located to both the cytoplasm and nuclei of neurons. It can be translocated to the nucleus through association with APBB1 (Fe65). Beta-APP42 associates with FRPL1 at the cell surface and the complex is then rapidly internalized. APP sorts to the basolateral surface in epithelial cells. During neuronal differentiation, the Thr-743 phosphorylated form is located mainly in growth cones, moderately in neurites and sparingly in the cell body. Casein kinase phosphorylation can occur either at the cell surface or within a post-Golgi compartment <ref>13</ref>

== 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>14<ref>

== References ==

1. Radzimanowski J, Simon B, Sattler M, Beyreuther K, Sinning I, Wild K. (2008) Structure of the intracellular domain of the amyloid precursor protein in complex with Fe65-PTB2. ''Embo Rep.'' v9 pp. 1134-40. [http://www.ncbi.nlm.nih.gov/pubmed/18833287?dopt=Abstract PMID 18833287]

2. Radzimanowski J, Simon B, Sattler M, Beyreuther K, Sinning I, Wild K. (2008) Structure of the intracellular domain of the amyloid precursor protein in complex with Fe65-PTB2. ''Embo Rep.'' v9 pp. 1134-40. [http://www.ncbi.nlm.nih.gov/pubmed/18833287?dopt=Abstract PMID 18833287]

3. Ando K, Iijima KI, Elliott JI, Kirino Y, Suzuki T. Phosphorylation-dependent regulation of the interaction of amyloid precursor protein with Fe65 affects the production of beta-amyloid.J Biol Chem. 2001 Oct 26;276(43):40353-61. Epub 2001 Aug 21. [http://www.ncbi.nlm.nih.gov/pubmed/11517218itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=5 PMID: 11517218]

4. Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The Alzheimer amyloid precursor protein (APP) and FE65, an APP-binding protein, regulate cell movement. J Cell Biol. 2001;153:1403–1414. [PubMed Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The Alzheimer amyloid precursor protein (APP) and FE65, an APP-binding protein, regulate cell movement. J Cell Biol. 2001;153:1403–1414. [PubMed PMID: 11425871

5. Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The amyloid precursor protein and its regulatory protein, FE65, in growth cones and synapses in vitro and in vivo. J Neurosci. 2003;23:5407–5415. [PubMed] 12843239

6. "Alzheimer's disease amyloid beta peptide 25-35 inhibits lipid peroxidation as a result of its membrane interactions."
Walter M.F., Mason P.E., Mason R.P.
Biochem. Biophys. Res. Commun. 233:760-764(1997) [PubMed: 9168929] [Abstract]
Cited for: FUNCTION OF BETA-AMYLOID PEPTIDE AS LIPID PEROXIDATION INHIBITOR, MUTAGENESIS OF MET-706.

7. "The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner."
Kimberly W.T., Zheng J.B., Guenette S.Y., Selkoe D.J.
J. Biol. Chem. 276:40288-40292(2001) [PubMed: 11544248] [Abstract]
Cited for: INTERACTION WITH APBB1, FUNCTION, SUBCELLULAR LOCATION.

8. "Direct interaction of soluble human recombinant tau protein with Abeta 1-42 results in tau aggregation and hyperphosphorylation by tau protein kinase II."
Rank K.B., Pauley A.M., Bhattacharya K., Wang Z., Evans D.B., Fleck T.J., Johnston J.A., Sharma S.K.
FEBS Lett. 514:263-268(2002) [PubMed: 11943163] [Abstract]
Cited for: INTERACTION WITH MAPT, FUNCTION.

9. "APP binds DR6 to trigger axon pruning and neuron death via distinct caspases."
Nikolaev A., McLaughlin T., O'Leary D.D.M., Tessier-Lavigne M.
Nature 457:981-989(2009) [PubMed: 19225519] [Abstract]
Cited for: FUNCTION, CLEAVAGE, INTERACTION WITH TNFRSF21.

10. [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]

11. http://www.ncbi.nlm.nih.gov/protein/Q9QXJ1.2?ordinalpos=6&itool=EntrezSystem2.PEntrez.Sequence.Sequence_ResultsPanel.Sequence_RVDocSum

12. http://www.ncbi.nlm.nih.gov/protein/Q9QXJ1.2?ordinalpos=6&itool=EntrezSystem2.PEntrez.Sequence.Sequence_ResultsPanel.Sequence_RVDocSum

13. "The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner."
Kimberly W.T., Zheng J.B., Guenette S.Y., Selkoe D.J.
J. Biol. Chem. 276:40288-40292(2001) [PubMed: 11544248] [Abstract]
Cited for: INTERACTION WITH APBB1, FUNCTION, SUBCELLULAR LOCATION.

14. 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]

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-10-31T19:47:07Z

Alexandra Balueva: /* APP and Alzheimer disease */

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-10-31T19:39:51Z

Alexandra Balueva:

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-10-31T19:29:35Z

Alexandra Balueva:

'''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>1</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 ==

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 et 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
<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>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> .

== 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>4</ref> <ref>5</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.

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>9</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].<ref>10</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 trancription activation activity. <ref>11</ref>

== Location ==
Fe65 could be located in cell membrane, cytoplasm, nucleus. In normal conditions, it mainly localizes to the cytoplasm, while a
small fraction is tethered to the cell membrane via its interaction with APP. Following exposure to DNA damaging agents, it is released
from cell membrane and translocates to the nucleus. Nuclear translocation is under the regulation of APP.<ref>12</ref>

Cell surface protein that rapidly becomes internalized via clathrin-coated pits. During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated). After alpha-secretase cleavage, soluble APP is released into the extracellular space and the C-terminal is internalized to endosomes and lysosomes. Some APP accumulates in secretory transport vesicles leaving the late Golgi compartment and returns to the cell surface. Gamma-CTF(59) peptide is located to both the cytoplasm and nuclei of neurons. It can be translocated to the nucleus through association with APBB1 (Fe65). Beta-APP42 associates with FRPL1 at the cell surface and the complex is then rapidly internalized. APP sorts to the basolateral surface in epithelial cells. During neuronal differentiation, the Thr-743 phosphorylated form is located mainly in growth cones, moderately in neurites and sparingly in the cell body. Casein kinase phosphorylation can occur either at the cell surface or within a post-Golgi compartment <ref>13</ref>

== 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>14<ref>

== References ==

1. Radzimanowski J, Simon B, Sattler M, Beyreuther K, Sinning I, Wild K. (2008) Structure of the intracellular domain of the amyloid precursor protein in complex with Fe65-PTB2. ''Embo Rep.'' v9 pp. 1134-40. [http://www.ncbi.nlm.nih.gov/pubmed/18833287?dopt=Abstract PMID 18833287]

2. Radzimanowski J, Simon B, Sattler M, Beyreuther K, Sinning I, Wild K. (2008) Structure of the intracellular domain of the amyloid precursor protein in complex with Fe65-PTB2. ''Embo Rep.'' v9 pp. 1134-40. [http://www.ncbi.nlm.nih.gov/pubmed/18833287?dopt=Abstract PMID 18833287]

3. Ando K, Iijima KI, Elliott JI, Kirino Y, Suzuki T. Phosphorylation-dependent regulation of the interaction of amyloid precursor protein with Fe65 affects the production of beta-amyloid.J Biol Chem. 2001 Oct 26;276(43):40353-61. Epub 2001 Aug 21. [http://www.ncbi.nlm.nih.gov/pubmed/11517218itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=5 PMID: 11517218]

4. Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The Alzheimer amyloid precursor protein (APP) and FE65, an APP-binding protein, regulate cell movement. J Cell Biol. 2001;153:1403–1414. [PubMed Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The Alzheimer amyloid precursor protein (APP) and FE65, an APP-binding protein, regulate cell movement. J Cell Biol. 2001;153:1403–1414. [PubMed PMID: 11425871

5. Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The amyloid precursor protein and its regulatory protein, FE65, in growth cones and synapses in vitro and in vivo. J Neurosci. 2003;23:5407–5415. [PubMed] 12843239

6. "Alzheimer's disease amyloid beta peptide 25-35 inhibits lipid peroxidation as a result of its membrane interactions."
Walter M.F., Mason P.E., Mason R.P.
Biochem. Biophys. Res. Commun. 233:760-764(1997) [PubMed: 9168929] [Abstract]
Cited for: FUNCTION OF BETA-AMYLOID PEPTIDE AS LIPID PEROXIDATION INHIBITOR, MUTAGENESIS OF MET-706.

7. "The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner."
Kimberly W.T., Zheng J.B., Guenette S.Y., Selkoe D.J.
J. Biol. Chem. 276:40288-40292(2001) [PubMed: 11544248] [Abstract]
Cited for: INTERACTION WITH APBB1, FUNCTION, SUBCELLULAR LOCATION.

8. "Direct interaction of soluble human recombinant tau protein with Abeta 1-42 results in tau aggregation and hyperphosphorylation by tau protein kinase II."
Rank K.B., Pauley A.M., Bhattacharya K., Wang Z., Evans D.B., Fleck T.J., Johnston J.A., Sharma S.K.
FEBS Lett. 514:263-268(2002) [PubMed: 11943163] [Abstract]
Cited for: INTERACTION WITH MAPT, FUNCTION.

9. "APP binds DR6 to trigger axon pruning and neuron death via distinct caspases."
Nikolaev A., McLaughlin T., O'Leary D.D.M., Tessier-Lavigne M.
Nature 457:981-989(2009) [PubMed: 19225519] [Abstract]
Cited for: FUNCTION, CLEAVAGE, INTERACTION WITH TNFRSF21.

10. [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]

11. http://www.ncbi.nlm.nih.gov/protein/Q9QXJ1.2?ordinalpos=6&itool=EntrezSystem2.PEntrez.Sequence.Sequence_ResultsPanel.Sequence_RVDocSum

12. http://www.ncbi.nlm.nih.gov/protein/Q9QXJ1.2?ordinalpos=6&itool=EntrezSystem2.PEntrez.Sequence.Sequence_ResultsPanel.Sequence_RVDocSum

13. "The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner."
Kimberly W.T., Zheng J.B., Guenette S.Y., Selkoe D.J.
J. Biol. Chem. 276:40288-40292(2001) [PubMed: 11544248] [Abstract]
Cited for: INTERACTION WITH APBB1, FUNCTION, SUBCELLULAR LOCATION.

14. 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]

== Further reading ==

[http://www.alzheimer.ca/english/index.php Alzheimer Society of Canada]

[http://www.alzheimer-adna.com/ Association pour le Développement des Neurosciences Appliquées]

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-10-31T19:28:07Z

Alexandra Balueva:

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-10-31T19:25:22Z

Alexandra Balueva:

'''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>1</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 ==

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 et 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
<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>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> .

== 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>4</ref> <ref>5</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.

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>9</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].<ref>10</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 trancription activation activity. <ref>11</ref>

== Location ==
Fe65 could be located in cell membrane, cytoplasm, nucleus. In normal conditions, it mainly localizes to the cytoplasm, while a
small fraction is tethered to the cell membrane via its interaction with APP. Following exposure to DNA damaging agents, it is released
from cell membrane and translocates to the nucleus. Nuclear translocation is under the regulation of APP.<ref>12</ref>

Cell surface protein that rapidly becomes internalized via clathrin-coated pits. During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated). After alpha-secretase cleavage, soluble APP is released into the extracellular space and the C-terminal is internalized to endosomes and lysosomes. Some APP accumulates in secretory transport vesicles leaving the late Golgi compartment and returns to the cell surface. Gamma-CTF(59) peptide is located to both the cytoplasm and nuclei of neurons. It can be translocated to the nucleus through association with APBB1 (Fe65). Beta-APP42 associates with FRPL1 at the cell surface and the complex is then rapidly internalized. APP sorts to the basolateral surface in epithelial cells. During neuronal differentiation, the Thr-743 phosphorylated form is located mainly in growth cones, moderately in neurites and sparingly in the cell body. Casein kinase phosphorylation can occur either at the cell surface or within a post-Golgi compartment <ref>13</ref>

== 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>14<ref>

== References ==

1. Radzimanowski J, Simon B, Sattler M, Beyreuther K, Sinning I, Wild K. (2008) Structure of the intracellular domain of the amyloid precursor protein in complex with Fe65-PTB2. ''Embo Rep.'' v9 pp. 1134-40. [http://www.ncbi.nlm.nih.gov/pubmed/18833287?dopt=Abstract PMID 18833287]

2. Radzimanowski J, Simon B, Sattler M, Beyreuther K, Sinning I, Wild K. (2008) Structure of the intracellular domain of the amyloid precursor protein in complex with Fe65-PTB2. ''Embo Rep.'' v9 pp. 1134-40. [http://www.ncbi.nlm.nih.gov/pubmed/18833287?dopt=Abstract PMID 18833287]

3. Ando K, Iijima KI, Elliott JI, Kirino Y, Suzuki T. Phosphorylation-dependent regulation of the interaction of amyloid precursor protein with Fe65 affects the production of beta-amyloid.J Biol Chem. 2001 Oct 26;276(43):40353-61. Epub 2001 Aug 21. [http://www.ncbi.nlm.nih.gov/pubmed/11517218itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=5 PMID: 11517218]

4. Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The Alzheimer amyloid precursor protein (APP) and FE65, an APP-binding protein, regulate cell movement. J Cell Biol. 2001;153:1403–1414. [PubMed Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The Alzheimer amyloid precursor protein (APP) and FE65, an APP-binding protein, regulate cell movement. J Cell Biol. 2001;153:1403–1414. [PubMed PMID: 11425871

5. Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The amyloid precursor protein and its regulatory protein, FE65, in growth cones and synapses in vitro and in vivo. J Neurosci. 2003;23:5407–5415. [PubMed] 12843239

6. "Alzheimer's disease amyloid beta peptide 25-35 inhibits lipid peroxidation as a result of its membrane interactions."
Walter M.F., Mason P.E., Mason R.P.
Biochem. Biophys. Res. Commun. 233:760-764(1997) [PubMed: 9168929] [Abstract]
Cited for: FUNCTION OF BETA-AMYLOID PEPTIDE AS LIPID PEROXIDATION INHIBITOR, MUTAGENESIS OF MET-706.

7. "The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner."
Kimberly W.T., Zheng J.B., Guenette S.Y., Selkoe D.J.
J. Biol. Chem. 276:40288-40292(2001) [PubMed: 11544248] [Abstract]
Cited for: INTERACTION WITH APBB1, FUNCTION, SUBCELLULAR LOCATION.

8. "Direct interaction of soluble human recombinant tau protein with Abeta 1-42 results in tau aggregation and hyperphosphorylation by tau protein kinase II."
Rank K.B., Pauley A.M., Bhattacharya K., Wang Z., Evans D.B., Fleck T.J., Johnston J.A., Sharma S.K.
FEBS Lett. 514:263-268(2002) [PubMed: 11943163] [Abstract]
Cited for: INTERACTION WITH MAPT, FUNCTION.

9. "APP binds DR6 to trigger axon pruning and neuron death via distinct caspases."
Nikolaev A., McLaughlin T., O'Leary D.D.M., Tessier-Lavigne M.
Nature 457:981-989(2009) [PubMed: 19225519] [Abstract]
Cited for: FUNCTION, CLEAVAGE, INTERACTION WITH TNFRSF21.

10. [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]

11. http://www.ncbi.nlm.nih.gov/protein/Q9QXJ1.2?ordinalpos=6&itool=EntrezSystem2.PEntrez.Sequence.Sequence_ResultsPanel.Sequence_RVDocSum

12. http://www.ncbi.nlm.nih.gov/protein/Q9QXJ1.2?ordinalpos=6&itool=EntrezSystem2.PEntrez.Sequence.Sequence_ResultsPanel.Sequence_RVDocSum

13. "The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner."
Kimberly W.T., Zheng J.B., Guenette S.Y., Selkoe D.J.
J. Biol. Chem. 276:40288-40292(2001) [PubMed: 11544248] [Abstract]
Cited for: INTERACTION WITH APBB1, FUNCTION, SUBCELLULAR LOCATION.

last one 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]

== Further reading ==
[http://www.alzheimer.ca/english/index.php Alzheimer Society of Canada]

[http://www.alzheimer-adna.com/ Association pour le Développement des Neurosciences Appliquées]

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-10-31T19:21:45Z

Alexandra Balueva:

'''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>1</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 ==

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 et 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
<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>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> .

== 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>4</ref> <ref>5</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.

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>9</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].<ref>10</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 trancription activation activity. <ref>11</ref>

== Location ==
Fe65 could be located in cell membrane, cytoplasm, nucleus. In normal conditions, it mainly localizes to the cytoplasm, while a
small fraction is tethered to the cell membrane via its interaction with APP. Following exposure to DNA damaging agents, it is released
from cell membrane and translocates to the nucleus. Nuclear translocation is under the regulation of APP.<ref>12</ref>

Cell surface protein that rapidly becomes internalized via clathrin-coated pits. During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated). After alpha-secretase cleavage, soluble APP is released into the extracellular space and the C-terminal is internalized to endosomes and lysosomes. Some APP accumulates in secretory transport vesicles leaving the late Golgi compartment and returns to the cell surface. Gamma-CTF(59) peptide is located to both the cytoplasm and nuclei of neurons. It can be translocated to the nucleus through association with APBB1 (Fe65). Beta-APP42 associates with FRPL1 at the cell surface and the complex is then rapidly internalized. APP sorts to the basolateral surface in epithelial cells. During neuronal differentiation, the Thr-743 phosphorylated form is located mainly in growth cones, moderately in neurites and sparingly in the cell body. Casein kinase phosphorylation can occur either at the cell surface or within a post-Golgi compartment <ref>13</ref>

== 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>14<ref>

== References ==

1. Radzimanowski J, Simon B, Sattler M, Beyreuther K, Sinning I, Wild K. (2008) Structure of the intracellular domain of the amyloid precursor protein in complex with Fe65-PTB2. ''Embo Rep.'' v9 pp. 1134-40. [http://www.ncbi.nlm.nih.gov/pubmed/18833287?dopt=Abstract PMID 18833287]

2. Radzimanowski J, Simon B, Sattler M, Beyreuther K, Sinning I, Wild K. (2008) Structure of the intracellular domain of the amyloid precursor protein in complex with Fe65-PTB2. ''Embo Rep.'' v9 pp. 1134-40. [http://www.ncbi.nlm.nih.gov/pubmed/18833287?dopt=Abstract PMID 18833287]

3. Ando K, Iijima KI, Elliott JI, Kirino Y, Suzuki T. Phosphorylation-dependent regulation of the interaction of amyloid precursor protein with Fe65 affects the production of beta-amyloid.J Biol Chem. 2001 Oct 26;276(43):40353-61. Epub 2001 Aug 21. [http://www.ncbi.nlm.nih.gov/pubmed/11517218itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=5 PMID: 11517218]

4. Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The Alzheimer amyloid precursor protein (APP) and FE65, an APP-binding protein, regulate cell movement. J Cell Biol. 2001;153:1403–1414. [PubMed Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The Alzheimer amyloid precursor protein (APP) and FE65, an APP-binding protein, regulate cell movement. J Cell Biol. 2001;153:1403–1414. [PubMed PMID: 11425871

5. Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The amyloid precursor protein and its regulatory protein, FE65, in growth cones and synapses in vitro and in vivo. J Neurosci. 2003;23:5407–5415. [PubMed] 12843239

6. "Alzheimer's disease amyloid beta peptide 25-35 inhibits lipid peroxidation as a result of its membrane interactions."
Walter M.F., Mason P.E., Mason R.P.
Biochem. Biophys. Res. Commun. 233:760-764(1997) [PubMed: 9168929] [Abstract]
Cited for: FUNCTION OF BETA-AMYLOID PEPTIDE AS LIPID PEROXIDATION INHIBITOR, MUTAGENESIS OF MET-706.

7. "The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner."
Kimberly W.T., Zheng J.B., Guenette S.Y., Selkoe D.J.
J. Biol. Chem. 276:40288-40292(2001) [PubMed: 11544248] [Abstract]
Cited for: INTERACTION WITH APBB1, FUNCTION, SUBCELLULAR LOCATION.

8. "Direct interaction of soluble human recombinant tau protein with Abeta 1-42 results in tau aggregation and hyperphosphorylation by tau protein kinase II."
Rank K.B., Pauley A.M., Bhattacharya K., Wang Z., Evans D.B., Fleck T.J., Johnston J.A., Sharma S.K.
FEBS Lett. 514:263-268(2002) [PubMed: 11943163] [Abstract]
Cited for: INTERACTION WITH MAPT, FUNCTION.

9. "APP binds DR6 to trigger axon pruning and neuron death via distinct caspases."
Nikolaev A., McLaughlin T., O'Leary D.D.M., Tessier-Lavigne M.
Nature 457:981-989(2009) [PubMed: 19225519] [Abstract]
Cited for: FUNCTION, CLEAVAGE, INTERACTION WITH TNFRSF21.

10. [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]

11. http://www.ncbi.nlm.nih.gov/protein/Q9QXJ1.2?ordinalpos=6&itool=EntrezSystem2.PEntrez.Sequence.Sequence_ResultsPanel.Sequence_RVDocSum

12. http://www.ncbi.nlm.nih.gov/protein/Q9QXJ1.2?ordinalpos=6&itool=EntrezSystem2.PEntrez.Sequence.Sequence_ResultsPanel.Sequence_RVDocSum

13. "The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner."
Kimberly W.T., Zheng J.B., Guenette S.Y., Selkoe D.J.
J. Biol. Chem. 276:40288-40292(2001) [PubMed: 11544248] [Abstract]
Cited for: INTERACTION WITH APBB1, FUNCTION, SUBCELLULAR LOCATION.

last one 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]

== Further reading ==
[http://www.alzheimer.ca/english/index.php Alzheimer Society of Canada]

[http://www.alzheimer-adna.com/ Association pour le Développement des Neurosciences Appliquées]

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-10-31T19:10:50Z

Alexandra Balueva: /* Functions of human APP and Fe65 protein */

'''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>1</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 ==

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 et 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
<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>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>

== Functions of human APP and Fe65 protein ==

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>

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.

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

== Location ==
Fe65 could be located in cell membrane, cytoplasm, nucleus. In normal conditions, it mainly localizes to the cytoplasm, while a
small fraction is tethered to the cell membrane via its interaction with APP. Following exposure to DNA damaging agents, it is released
from cell membrane and translocates to the nucleus. Nuclear translocation is under the regulation of APP.
http://www.ncbi.nlm.nih.gov/protein/Q9QXJ1.2?ordinalpos=6&itool=EntrezSystem2.PEntrez.Sequence.Sequence_ResultsPanel.Sequence_RVDocSum

Cell surface protein that rapidly becomes internalized via clathrin-coated pits. During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated). After alpha-secretase cleavage, soluble APP is released into the extracellular space and the C-terminal is internalized to endosomes and lysosomes. Some APP accumulates in secretory transport vesicles leaving the late Golgi compartment and returns to the cell surface. Gamma-CTF(59) peptide is located to both the cytoplasm and nuclei of neurons. It can be translocated to the nucleus through association with APBB1 (Fe65). Beta-APP42 associates with FRPL1 at the cell surface and the complex is then rapidly internalized. APP sorts to the basolateral surface in epithelial cells. During neuronal differentiation, the Thr-743 phosphorylated form is located mainly in growth cones, moderately in neurites and sparingly in the cell body. Casein kinase phosphorylation can occur either at the cell surface or within a post-Golgi compartment "The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner."
Kimberly W.T., Zheng J.B., Guenette S.Y., Selkoe D.J.
J. Biol. Chem. 276:40288-40292(2001) [PubMed: 11544248] [Abstract]
Cited for: INTERACTION WITH APBB1, FUNCTION, SUBCELLULAR LOCATION.

== 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. Ref4

== References ==

1. Radzimanowski J, Simon B, Sattler M, Beyreuther K, Sinning I, Wild K. (2008) Structure of the intracellular domain of the amyloid precursor protein in complex with Fe65-PTB2. ''Embo Rep.'' v9 pp. 1134-40. [http://www.ncbi.nlm.nih.gov/pubmed/18833287?dopt=Abstract PMID 18833287]

2. Radzimanowski J, Simon B, Sattler M, Beyreuther K, Sinning I, Wild K. (2008) Structure of the intracellular domain of the amyloid precursor protein in complex with Fe65-PTB2. ''Embo Rep.'' v9 pp. 1134-40. [http://www.ncbi.nlm.nih.gov/pubmed/18833287?dopt=Abstract PMID 18833287]

3. Ando K, Iijima KI, Elliott JI, Kirino Y, Suzuki T. Phosphorylation-dependent regulation of the interaction of amyloid precursor protein with Fe65 affects the production of beta-amyloid.J Biol Chem. 2001 Oct 26;276(43):40353-61. Epub 2001 Aug 21. [http://www.ncbi.nlm.nih.gov/pubmed/11517218itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=5 PMID: 11517218]

4. Priller C, Bauer T, Mitteregger G, Krebs B, Kretzschmar HA, Herms J. (2006). Synapse formation and function is modulated by the amyloid precursor protein. J Neurosci 26(27):7212-21 [http://www.ncbi.nlm.nih.gov/pubmed/16822978 PMID: 16822978]

5. Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The Alzheimer amyloid precursor protein (APP) and FE65, an APP-binding protein, regulate cell movement. J Cell Biol. 2001;153:1403–1414. [PubMed Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The Alzheimer amyloid precursor protein (APP) and FE65, an APP-binding protein, regulate cell movement. J Cell Biol. 2001;153:1403–1414. [PubMed PMID: 11425871

6. Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The amyloid precursor protein and its regulatory protein, FE65, in growth cones and synapses in vitro and in vivo. J Neurosci. 2003;23:5407–5415. [PubMed] 12843239

9. [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]

last one 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]

== Further reading ==
[http://www.alzheimer.ca/english/index.php Alzheimer Society of Canada]

[http://www.alzheimer-adna.com/ Association pour le Développement des Neurosciences Appliquées]

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-10-31T19:06:01Z

Alexandra Balueva: /* References */

'''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>1</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 ==

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 et 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
<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>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>

== Functions of human APP and Fe65 protein ==

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>

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

== Location ==
Fe65 could be located in cell membrane, cytoplasm, nucleus. In normal conditions, it mainly localizes to the cytoplasm, while a
small fraction is tethered to the cell membrane via its interaction with APP. Following exposure to DNA damaging agents, it is released
from cell membrane and translocates to the nucleus. Nuclear translocation is under the regulation of APP.
http://www.ncbi.nlm.nih.gov/protein/Q9QXJ1.2?ordinalpos=6&itool=EntrezSystem2.PEntrez.Sequence.Sequence_ResultsPanel.Sequence_RVDocSum

Cell surface protein that rapidly becomes internalized via clathrin-coated pits. During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated). After alpha-secretase cleavage, soluble APP is released into the extracellular space and the C-terminal is internalized to endosomes and lysosomes. Some APP accumulates in secretory transport vesicles leaving the late Golgi compartment and returns to the cell surface. Gamma-CTF(59) peptide is located to both the cytoplasm and nuclei of neurons. It can be translocated to the nucleus through association with APBB1 (Fe65). Beta-APP42 associates with FRPL1 at the cell surface and the complex is then rapidly internalized. APP sorts to the basolateral surface in epithelial cells. During neuronal differentiation, the Thr-743 phosphorylated form is located mainly in growth cones, moderately in neurites and sparingly in the cell body. Casein kinase phosphorylation can occur either at the cell surface or within a post-Golgi compartment "The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner."
Kimberly W.T., Zheng J.B., Guenette S.Y., Selkoe D.J.
J. Biol. Chem. 276:40288-40292(2001) [PubMed: 11544248] [Abstract]
Cited for: INTERACTION WITH APBB1, FUNCTION, SUBCELLULAR LOCATION.

== 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. Ref4

== References ==

1. Radzimanowski J, Simon B, Sattler M, Beyreuther K, Sinning I, Wild K. (2008) Structure of the intracellular domain of the amyloid precursor protein in complex with Fe65-PTB2. ''Embo Rep.'' v9 pp. 1134-40. [http://www.ncbi.nlm.nih.gov/pubmed/18833287?dopt=Abstract PMID 18833287]

2. Radzimanowski J, Simon B, Sattler M, Beyreuther K, Sinning I, Wild K. (2008) Structure of the intracellular domain of the amyloid precursor protein in complex with Fe65-PTB2. ''Embo Rep.'' v9 pp. 1134-40. [http://www.ncbi.nlm.nih.gov/pubmed/18833287?dopt=Abstract PMID 18833287]

3. Ando K, Iijima KI, Elliott JI, Kirino Y, Suzuki T. Phosphorylation-dependent regulation of the interaction of amyloid precursor protein with Fe65 affects the production of beta-amyloid.J Biol Chem. 2001 Oct 26;276(43):40353-61. Epub 2001 Aug 21. [http://www.ncbi.nlm.nih.gov/pubmed/11517218itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=5 PMID: 11517218]

4. Priller C, Bauer T, Mitteregger G, Krebs B, Kretzschmar HA, Herms J. (2006). Synapse formation and function is modulated by the amyloid precursor protein. J Neurosci 26(27):7212-21 [http://www.ncbi.nlm.nih.gov/pubmed/16822978 PMID: 16822978]

5. Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The Alzheimer amyloid precursor protein (APP) and FE65, an APP-binding protein, regulate cell movement. J Cell Biol. 2001;153:1403–1414. [PubMed Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The Alzheimer amyloid precursor protein (APP) and FE65, an APP-binding protein, regulate cell movement. J Cell Biol. 2001;153:1403–1414. [PubMed PMID: 11425871

6. Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The amyloid precursor protein and its regulatory protein, FE65, in growth cones and synapses in vitro and in vivo. J Neurosci. 2003;23:5407–5415. [PubMed] 12843239

9. [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]

last one 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]

== Further reading ==
[http://www.alzheimer.ca/english/index.php Alzheimer Society of Canada]

[http://www.alzheimer-adna.com/ Association pour le Développement des Neurosciences Appliquées]

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-10-31T19:05:28Z

Alexandra Balueva: /* Functions of human APP and Fe65 protein */

'''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>1</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 ==

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 et 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
<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>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>

== Functions of human APP and Fe65 protein ==

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>

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

== Location ==
Fe65 could be located in cell membrane, cytoplasm, nucleus. In normal conditions, it mainly localizes to the cytoplasm, while a
small fraction is tethered to the cell membrane via its interaction with APP. Following exposure to DNA damaging agents, it is released
from cell membrane and translocates to the nucleus. Nuclear translocation is under the regulation of APP.
http://www.ncbi.nlm.nih.gov/protein/Q9QXJ1.2?ordinalpos=6&itool=EntrezSystem2.PEntrez.Sequence.Sequence_ResultsPanel.Sequence_RVDocSum

Cell surface protein that rapidly becomes internalized via clathrin-coated pits. During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated). After alpha-secretase cleavage, soluble APP is released into the extracellular space and the C-terminal is internalized to endosomes and lysosomes. Some APP accumulates in secretory transport vesicles leaving the late Golgi compartment and returns to the cell surface. Gamma-CTF(59) peptide is located to both the cytoplasm and nuclei of neurons. It can be translocated to the nucleus through association with APBB1 (Fe65). Beta-APP42 associates with FRPL1 at the cell surface and the complex is then rapidly internalized. APP sorts to the basolateral surface in epithelial cells. During neuronal differentiation, the Thr-743 phosphorylated form is located mainly in growth cones, moderately in neurites and sparingly in the cell body. Casein kinase phosphorylation can occur either at the cell surface or within a post-Golgi compartment "The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner."
Kimberly W.T., Zheng J.B., Guenette S.Y., Selkoe D.J.
J. Biol. Chem. 276:40288-40292(2001) [PubMed: 11544248] [Abstract]
Cited for: INTERACTION WITH APBB1, FUNCTION, SUBCELLULAR LOCATION.

== 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. Ref4

== References ==

1. Radzimanowski J, Simon B, Sattler M, Beyreuther K, Sinning I, Wild K. (2008) Structure of the intracellular domain of the amyloid precursor protein in complex with Fe65-PTB2. ''Embo Rep.'' v9 pp. 1134-40. [http://www.ncbi.nlm.nih.gov/pubmed/18833287?dopt=Abstract PMID 18833287]

2. Radzimanowski J, Simon B, Sattler M, Beyreuther K, Sinning I, Wild K. (2008) Structure of the intracellular domain of the amyloid precursor protein in complex with Fe65-PTB2. ''Embo Rep.'' v9 pp. 1134-40. [http://www.ncbi.nlm.nih.gov/pubmed/18833287?dopt=Abstract PMID 18833287]

3. Ando K, Iijima KI, Elliott JI, Kirino Y, Suzuki T. Phosphorylation-dependent regulation of the interaction of amyloid precursor protein with Fe65 affects the production of beta-amyloid.J Biol Chem. 2001 Oct 26;276(43):40353-61. Epub 2001 Aug 21. [http://www.ncbi.nlm.nih.gov/pubmed/11517218itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=5 PMID: 11517218]

4. Priller C, Bauer T, Mitteregger G, Krebs B, Kretzschmar HA, Herms J. (2006). Synapse formation and function is modulated by the amyloid precursor protein. J Neurosci 26(27):7212-21 [http://www.ncbi.nlm.nih.gov/pubmed/16822978 PMID: 16822978]

5. Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The Alzheimer amyloid precursor protein (APP) and FE65, an APP-binding protein, regulate cell movement. J Cell Biol. 2001;153:1403–1414. [PubMed Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The Alzheimer amyloid precursor protein (APP) and FE65, an APP-binding protein, regulate cell movement. J Cell Biol. 2001;153:1403–1414. [PubMed PMID: 11425871

6. Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The amyloid precursor protein and its regulatory protein, FE65, in growth cones and synapses in vitro and in vivo. J Neurosci. 2003;23:5407–5415. [PubMed] 12843239

8. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1538601/?tool=pubmed

9. [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]

last one 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]

== Further reading ==
[http://www.alzheimer.ca/english/index.php Alzheimer Society of Canada]

[http://www.alzheimer-adna.com/ Association pour le Développement des Neurosciences Appliquées]

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-10-31T19:00:17Z

Alexandra Balueva: /* References */

'''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>1</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 ==

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 et 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
<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>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>

== Functions of human APP and Fe65 protein ==

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>

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

== Location ==
Fe65 could be located in cell membrane, cytoplasm, nucleus. In normal conditions, it mainly localizes to the cytoplasm, while a
small fraction is tethered to the cell membrane via its interaction with APP. Following exposure to DNA damaging agents, it is released
from cell membrane and translocates to the nucleus. Nuclear translocation is under the regulation of APP.
http://www.ncbi.nlm.nih.gov/protein/Q9QXJ1.2?ordinalpos=6&itool=EntrezSystem2.PEntrez.Sequence.Sequence_ResultsPanel.Sequence_RVDocSum

Cell surface protein that rapidly becomes internalized via clathrin-coated pits. During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated). After alpha-secretase cleavage, soluble APP is released into the extracellular space and the C-terminal is internalized to endosomes and lysosomes. Some APP accumulates in secretory transport vesicles leaving the late Golgi compartment and returns to the cell surface. Gamma-CTF(59) peptide is located to both the cytoplasm and nuclei of neurons. It can be translocated to the nucleus through association with APBB1 (Fe65). Beta-APP42 associates with FRPL1 at the cell surface and the complex is then rapidly internalized. APP sorts to the basolateral surface in epithelial cells. During neuronal differentiation, the Thr-743 phosphorylated form is located mainly in growth cones, moderately in neurites and sparingly in the cell body. Casein kinase phosphorylation can occur either at the cell surface or within a post-Golgi compartment "The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner."
Kimberly W.T., Zheng J.B., Guenette S.Y., Selkoe D.J.
J. Biol. Chem. 276:40288-40292(2001) [PubMed: 11544248] [Abstract]
Cited for: INTERACTION WITH APBB1, FUNCTION, SUBCELLULAR LOCATION.

== 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. Ref4

== References ==

1. Radzimanowski J, Simon B, Sattler M, Beyreuther K, Sinning I, Wild K. (2008) Structure of the intracellular domain of the amyloid precursor protein in complex with Fe65-PTB2. ''Embo Rep.'' v9 pp. 1134-40. [http://www.ncbi.nlm.nih.gov/pubmed/18833287?dopt=Abstract PMID 18833287]

2. Radzimanowski J, Simon B, Sattler M, Beyreuther K, Sinning I, Wild K. (2008) Structure of the intracellular domain of the amyloid precursor protein in complex with Fe65-PTB2. ''Embo Rep.'' v9 pp. 1134-40. [http://www.ncbi.nlm.nih.gov/pubmed/18833287?dopt=Abstract PMID 18833287]

3. Ando K, Iijima KI, Elliott JI, Kirino Y, Suzuki T. Phosphorylation-dependent regulation of the interaction of amyloid precursor protein with Fe65 affects the production of beta-amyloid.J Biol Chem. 2001 Oct 26;276(43):40353-61. Epub 2001 Aug 21. [http://www.ncbi.nlm.nih.gov/pubmed/11517218itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=5 PMID: 11517218]

4. Priller C, Bauer T, Mitteregger G, Krebs B, Kretzschmar HA, Herms J. (2006). Synapse formation and function is modulated by the amyloid precursor protein. J Neurosci 26(27):7212-21 [http://www.ncbi.nlm.nih.gov/pubmed/16822978 PMID: 16822978]

5. Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The Alzheimer amyloid precursor protein (APP) and FE65, an APP-binding protein, regulate cell movement. J Cell Biol. 2001;153:1403–1414. [PubMed Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The Alzheimer amyloid precursor protein (APP) and FE65, an APP-binding protein, regulate cell movement. J Cell Biol. 2001;153:1403–1414. [PubMed PMID: 11425871

6. Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The amyloid precursor protein and its regulatory protein, FE65, in growth cones and synapses in vitro and in vivo. J Neurosci. 2003;23:5407–5415. [PubMed] 12843239

8. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1538601/?tool=pubmed

9. [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]

last one 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]

== Further reading ==
[http://www.alzheimer.ca/english/index.php Alzheimer Society of Canada]

[http://www.alzheimer-adna.com/ Association pour le Développement des Neurosciences Appliquées]

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-10-31T18:55:04Z

Alexandra Balueva: /* References */

'''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>1</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 ==

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 et 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
<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>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>

== Functions of human APP and Fe65 protein ==

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>

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

== Location ==
Fe65 could be located in cell membrane, cytoplasm, nucleus. In normal conditions, it mainly localizes to the cytoplasm, while a
small fraction is tethered to the cell membrane via its interaction with APP. Following exposure to DNA damaging agents, it is released
from cell membrane and translocates to the nucleus. Nuclear translocation is under the regulation of APP.
http://www.ncbi.nlm.nih.gov/protein/Q9QXJ1.2?ordinalpos=6&itool=EntrezSystem2.PEntrez.Sequence.Sequence_ResultsPanel.Sequence_RVDocSum

Cell surface protein that rapidly becomes internalized via clathrin-coated pits. During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated). After alpha-secretase cleavage, soluble APP is released into the extracellular space and the C-terminal is internalized to endosomes and lysosomes. Some APP accumulates in secretory transport vesicles leaving the late Golgi compartment and returns to the cell surface. Gamma-CTF(59) peptide is located to both the cytoplasm and nuclei of neurons. It can be translocated to the nucleus through association with APBB1 (Fe65). Beta-APP42 associates with FRPL1 at the cell surface and the complex is then rapidly internalized. APP sorts to the basolateral surface in epithelial cells. During neuronal differentiation, the Thr-743 phosphorylated form is located mainly in growth cones, moderately in neurites and sparingly in the cell body. Casein kinase phosphorylation can occur either at the cell surface or within a post-Golgi compartment "The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner."
Kimberly W.T., Zheng J.B., Guenette S.Y., Selkoe D.J.
J. Biol. Chem. 276:40288-40292(2001) [PubMed: 11544248] [Abstract]
Cited for: INTERACTION WITH APBB1, FUNCTION, SUBCELLULAR LOCATION.

== 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. Ref4

== References ==

1. Radzimanowski J, Simon B, Sattler M, Beyreuther K, Sinning I, Wild K. (2008) Structure of the intracellular domain of the amyloid precursor protein in complex with Fe65-PTB2. ''Embo Rep.'' v9 pp. 1134-40. [http://www.ncbi.nlm.nih.gov/pubmed/18833287?dopt=Abstract PMID 18833287]

2. Radzimanowski J, Simon B, Sattler M, Beyreuther K, Sinning I, Wild K. (2008) Structure of the intracellular domain of the amyloid precursor protein in complex with Fe65-PTB2. ''Embo Rep.'' v9 pp. 1134-40. [http://www.ncbi.nlm.nih.gov/pubmed/18833287?dopt=Abstract PMID 18833287]

3. Ando K, Iijima KI, Elliott JI, Kirino Y, Suzuki T. Phosphorylation-dependent regulation of the interaction of amyloid precursor protein with Fe65 affects the production of beta-amyloid.J Biol Chem. 2001 Oct 26;276(43):40353-61. Epub 2001 Aug 21. [http://www.ncbi.nlm.nih.gov/pubmed/11517218itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=5 PMID: 11517218]

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]

4. Priller C, Bauer T, Mitteregger G, Krebs B, Kretzschmar HA, Herms J. (2006). Synapse formation and function is modulated by the amyloid precursor protein. J Neurosci 26(27):7212-21 [http://www.ncbi.nlm.nih.gov/pubmed/16822978 PMID: 16822978]

5. Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The Alzheimer amyloid precursor protein (APP) and FE65, an APP-binding protein, regulate cell movement. J Cell Biol. 2001;153:1403–1414. [PubMed Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The Alzheimer amyloid precursor protein (APP) and FE65, an APP-binding protein, regulate cell movement. J Cell Biol. 2001;153:1403–1414. [PubMed PMID: 11425871

6. Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The amyloid precursor protein and its regulatory protein, FE65, in growth cones and synapses in vitro and in vivo. J Neurosci. 2003;23:5407–5415. [PubMed] 12843239

8. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1538601/?tool=pubmed

9. [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]

== Further reading ==
[http://www.alzheimer.ca/english/index.php Alzheimer Society of Canada]

[http://www.alzheimer-adna.com/ Association pour le Développement des Neurosciences Appliquées]

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-10-31T18:53:07Z

Alexandra Balueva: /* References */

'''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>1</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 ==

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 et 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
<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>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>

== Functions of human APP and Fe65 protein ==

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>

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

== Location ==
Fe65 could be located in cell membrane, cytoplasm, nucleus. In normal conditions, it mainly localizes to the cytoplasm, while a
small fraction is tethered to the cell membrane via its interaction with APP. Following exposure to DNA damaging agents, it is released
from cell membrane and translocates to the nucleus. Nuclear translocation is under the regulation of APP.
http://www.ncbi.nlm.nih.gov/protein/Q9QXJ1.2?ordinalpos=6&itool=EntrezSystem2.PEntrez.Sequence.Sequence_ResultsPanel.Sequence_RVDocSum

Cell surface protein that rapidly becomes internalized via clathrin-coated pits. During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated). After alpha-secretase cleavage, soluble APP is released into the extracellular space and the C-terminal is internalized to endosomes and lysosomes. Some APP accumulates in secretory transport vesicles leaving the late Golgi compartment and returns to the cell surface. Gamma-CTF(59) peptide is located to both the cytoplasm and nuclei of neurons. It can be translocated to the nucleus through association with APBB1 (Fe65). Beta-APP42 associates with FRPL1 at the cell surface and the complex is then rapidly internalized. APP sorts to the basolateral surface in epithelial cells. During neuronal differentiation, the Thr-743 phosphorylated form is located mainly in growth cones, moderately in neurites and sparingly in the cell body. Casein kinase phosphorylation can occur either at the cell surface or within a post-Golgi compartment "The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner."
Kimberly W.T., Zheng J.B., Guenette S.Y., Selkoe D.J.
J. Biol. Chem. 276:40288-40292(2001) [PubMed: 11544248] [Abstract]
Cited for: INTERACTION WITH APBB1, FUNCTION, SUBCELLULAR LOCATION.

== 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. Ref4

== References ==

1. Radzimanowski J, Simon B, Sattler M, Beyreuther K, Sinning I, Wild K. (2008) Structure of the intracellular domain of the amyloid precursor protein in complex with Fe65-PTB2. ''Embo Rep.'' v9 pp. 1134-40. [http://www.ncbi.nlm.nih.gov/pubmed/18833287?dopt=Abstract PMID 18833287]

2. Radzimanowski J, Simon B, Sattler M, Beyreuther K, Sinning I, Wild K. (2008) Structure of the intracellular domain of the amyloid precursor protein in complex with Fe65-PTB2. ''Embo Rep.'' v9 pp. 1134-40. [http://www.ncbi.nlm.nih.gov/pubmed/18833287?dopt=Abstract PMID 18833287]

3. Ando K, Iijima KI, Elliott JI, Kirino Y, Suzuki T. Phosphorylation-dependent regulation of the interaction of amyloid precursor protein with Fe65 affects the production of beta-amyloid.J Biol Chem. 2001 Oct 26;276(43):40353-61. Epub 2001 Aug 21. [http://www.ncbi.nlm.nih.gov/pubmed/11517218itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=5 PMID: 11517218]

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]

4. Priller C, Bauer T, Mitteregger G, Krebs B, Kretzschmar HA, Herms J. (2006). Synapse formation and function is modulated by the amyloid precursor protein. J Neurosci 26(27):7212-21 [http://www.ncbi.nlm.nih.gov/pubmed/16822978 PMID: 16822978]

6. Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The Alzheimer amyloid precursor protein (APP) and FE65, an APP-binding protein, regulate cell movement. J Cell Biol. 2001;153:1403–1414. [PubMed Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The Alzheimer amyloid precursor protein (APP) and FE65, an APP-binding protein, regulate cell movement. J Cell Biol. 2001;153:1403–1414. [PubMed PMID: 11425871

7. Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The amyloid precursor protein and its regulatory protein, FE65, in growth cones and synapses in vitro and in vivo. J Neurosci. 2003;23:5407–5415. [PubMed] 12843239

8. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1538601/?tool=pubmed

9. [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]

== Further reading ==
[http://www.alzheimer.ca/english/index.php Alzheimer Society of Canada]

[http://www.alzheimer-adna.com/ Association pour le Développement des Neurosciences Appliquées]

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-10-31T18:45:14Z

Alexandra Balueva: /* Location */

'''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>1</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 ==

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 et 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
<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>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>

== Functions of human APP and Fe65 protein ==

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>

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

== Location ==
Fe65 could be located in cell membrane, cytoplasm, nucleus. In normal conditions, it mainly localizes to the cytoplasm, while a
small fraction is tethered to the cell membrane via its interaction with APP. Following exposure to DNA damaging agents, it is released
from cell membrane and translocates to the nucleus. Nuclear translocation is under the regulation of APP.
http://www.ncbi.nlm.nih.gov/protein/Q9QXJ1.2?ordinalpos=6&itool=EntrezSystem2.PEntrez.Sequence.Sequence_ResultsPanel.Sequence_RVDocSum

Cell surface protein that rapidly becomes internalized via clathrin-coated pits. During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated). After alpha-secretase cleavage, soluble APP is released into the extracellular space and the C-terminal is internalized to endosomes and lysosomes. Some APP accumulates in secretory transport vesicles leaving the late Golgi compartment and returns to the cell surface. Gamma-CTF(59) peptide is located to both the cytoplasm and nuclei of neurons. It can be translocated to the nucleus through association with APBB1 (Fe65). Beta-APP42 associates with FRPL1 at the cell surface and the complex is then rapidly internalized. APP sorts to the basolateral surface in epithelial cells. During neuronal differentiation, the Thr-743 phosphorylated form is located mainly in growth cones, moderately in neurites and sparingly in the cell body. Casein kinase phosphorylation can occur either at the cell surface or within a post-Golgi compartment "The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner."
Kimberly W.T., Zheng J.B., Guenette S.Y., Selkoe D.J.
J. Biol. Chem. 276:40288-40292(2001) [PubMed: 11544248] [Abstract]
Cited for: INTERACTION WITH APBB1, FUNCTION, SUBCELLULAR LOCATION.

== 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. Ref4

== References ==

1. Radzimanowski J, Simon B, Sattler M, Beyreuther K, Sinning I, Wild K. (2008) Structure of the intracellular domain of the amyloid precursor protein in complex with Fe65-PTB2. ''Embo Rep.'' v9 pp. 1134-40. [http://www.ncbi.nlm.nih.gov/pubmed/18833287?dopt=Abstract PMID 18833287]

2. Radzimanowski J, Simon B, Sattler M, Beyreuther K, Sinning I, Wild K. (2008) Structure of the intracellular domain of the amyloid precursor protein in complex with Fe65-PTB2. ''Embo Rep.'' v9 pp. 1134-40. [http://www.ncbi.nlm.nih.gov/pubmed/18833287?dopt=Abstract PMID 18833287]

3. Ando K, Iijima KI, Elliott JI, Kirino Y, Suzuki T. Phosphorylation-dependent regulation of the interaction of amyloid precursor protein with Fe65 affects the production of beta-amyloid.J Biol Chem. 2001 Oct 26;276(43):40353-61. Epub 2001 Aug 21. [http://www.ncbi.nlm.nih.gov/pubmed/11517218itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=5 PMID: 11517218]

4. 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]

5. Priller C, Bauer T, Mitteregger G, Krebs B, Kretzschmar HA, Herms J. (2006). Synapse formation and function is modulated by the amyloid precursor protein. J Neurosci 26(27):7212-21 [http://www.ncbi.nlm.nih.gov/pubmed/16822978 PMID: 16822978]

6. Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The Alzheimer amyloid precursor protein (APP) and FE65, an APP-binding protein, regulate cell movement. J Cell Biol. 2001;153:1403–1414. [PubMed Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The Alzheimer amyloid precursor protein (APP) and FE65, an APP-binding protein, regulate cell movement. J Cell Biol. 2001;153:1403–1414. [PubMed PMID: 11425871

7. Sabo SL, Ikin AF, Buxbaum JD, Greengard P. The amyloid precursor protein and its regulatory protein, FE65, in growth cones and synapses in vitro and in vivo. J Neurosci. 2003;23:5407–5415. [PubMed] 12843239

8. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1538601/?tool=pubmed

9. [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]

== Further reading ==
[http://www.alzheimer.ca/english/index.php Alzheimer Society of Canada]

[http://www.alzheimer-adna.com/ Association pour le Développement des Neurosciences Appliquées]

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-10-31T18:39:33Z

Alexandra Balueva: /* Location */

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-10-31T18:27:24Z

Alexandra Balueva:

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-10-31T18:26:09Z

Alexandra Balueva:

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-10-31T18:23:12Z

Alexandra Balueva: /* Structure */

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-10-31T18:22:29Z

Alexandra Balueva:

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-10-31T18:21:40Z

Alexandra Balueva:

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-10-31T18:20:56Z

Alexandra Balueva:

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-10-31T18:12:08Z

Alexandra Balueva: /* Structure */

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-10-31T18:07:47Z

Alexandra Balueva:

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-10-31T17:31:33Z

Alexandra Balueva: ti

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-10-31T17:21:08Z

Alexandra Balueva:

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-10-31T17:16:59Z

Alexandra Balueva:

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-10-31T17:16:16Z

Alexandra Balueva:

Human APP Intracellular Domain Complex with Fe65-PTB2

2009-10-31T17:05:04Z

Alexandra Balueva: