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5myk

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Structure of Pyroglutamate-Abeta-specific Fab c#17 in complex with murine Abeta-pE3-18PEGb

Structural highlights

5myk is a 3 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.6Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

A4_MOUSE Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis. Involved in cell mobility and transcription regulation through protein-protein interactions. Can promote transcription activation through binding to APBB1-KAT5 and inhibit 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. May be involved in copper homeostasis/oxidative stress through copper ion reduction. Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV (By similarity). The splice isoforms that contain the BPTI domain possess protease inhibitor activity. Induces a AGER-dependent pathway that involves activation of p38 MAPK, resulting in internalization of amyloid-beta peptide and leading to mitochondrial dysfunction in cultured cortical neurons (By similarity). Provides Cu(2+) ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1.^[1] Beta-amyloid peptides are lipophilic metal chelators with metal-reducing activity. Binds transient metals such as copper, zinc and iron. Rat and mouse beta-amyloid peptides bind only weakly transient metals and have little reducing activity due to substitutions of transient metal chelating residues. Beta-APP42 may activate mononuclear phagocytes in the brain and elicit inflammatory responses. Promotes both tau aggregation and TPK II-mediated phosphorylation. Also bind GPC1 in lipid rafts (By similarity).^[2] The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis.^[3] N-APP binds TNFRSF21 triggering caspase activation and degeneration of both neuronal cell bodies (via caspase-3) and axons (via caspase-6) (By similarity).^[4]

Publication Abstract from PubMed

Alzheimer disease is associated with deposition of the amyloidogenic peptide Abeta in the brain. Passive immunization using Abeta-specific antibodies has been demonstrated to reduce amyloid deposition both in vitro and in vivo Because N-terminally truncated pyroglutamate (pE)-modified Abeta species (AbetapE3) exhibit enhanced aggregation potential and propensity to form toxic oligomers, they represent particularly attractive targets for antibody therapy. Here we present three separate monoclonal antibodies that specifically recognize AbetapE3 with affinities of 1-10 nm and inhibit AbetapE3 fibril formation in vitro. In vivo application of one of these resulted in improved memory in AbetapE3 oligomer-treated mice. Crystal structures of Fab-AbetapE3 complexes revealed two distinct binding modes for the peptide. Juxtaposition of pyroglutamate pE3 and the F4 side chain (the "pEF head") confers a pronounced bulky hydrophobic nature to the AbetapE3 N terminus that might explain the enhanced aggregation properties of the modified peptide. The deep burial of the pEF head by two of the antibodies explains their high target specificity and low cross-reactivity, making them promising candidates for the development of clinical antibodies.

Structural and functional analyses of pyroglutamate-amyloid-beta-specific antibodies as a basis for Alzheimer immunotherapy.,Piechotta A, Parthier C, Kleinschmidt M, Gnoth K, Pillot T, Lues I, Demuth HU, Schilling S, Rahfeld JU, Stubbs MT J Biol Chem. 2017 Jul 28;292(30):12713-12724. doi: 10.1074/jbc.M117.777839. Epub , 2017 Jun 16. PMID:28623233^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Cappai R, Cheng F, Ciccotosto GD, Needham BE, Masters CL, Multhaup G, Fransson LA, Mani K. The amyloid precursor protein (APP) of Alzheimer disease and its paralog, APLP2, modulate the Cu/Zn-Nitric Oxide-catalyzed degradation of glypican-1 heparan sulfate in vivo. J Biol Chem. 2005 Apr 8;280(14):13913-20. Epub 2005 Jan 27. PMID:15677459 doi:http://dx.doi.org/10.1074/jbc.M409179200
↑ Cappai R, Cheng F, Ciccotosto GD, Needham BE, Masters CL, Multhaup G, Fransson LA, Mani K. The amyloid precursor protein (APP) of Alzheimer disease and its paralog, APLP2, modulate the Cu/Zn-Nitric Oxide-catalyzed degradation of glypican-1 heparan sulfate in vivo. J Biol Chem. 2005 Apr 8;280(14):13913-20. Epub 2005 Jan 27. PMID:15677459 doi:http://dx.doi.org/10.1074/jbc.M409179200
↑ Cappai R, Cheng F, Ciccotosto GD, Needham BE, Masters CL, Multhaup G, Fransson LA, Mani K. The amyloid precursor protein (APP) of Alzheimer disease and its paralog, APLP2, modulate the Cu/Zn-Nitric Oxide-catalyzed degradation of glypican-1 heparan sulfate in vivo. J Biol Chem. 2005 Apr 8;280(14):13913-20. Epub 2005 Jan 27. PMID:15677459 doi:http://dx.doi.org/10.1074/jbc.M409179200
↑ Cappai R, Cheng F, Ciccotosto GD, Needham BE, Masters CL, Multhaup G, Fransson LA, Mani K. The amyloid precursor protein (APP) of Alzheimer disease and its paralog, APLP2, modulate the Cu/Zn-Nitric Oxide-catalyzed degradation of glypican-1 heparan sulfate in vivo. J Biol Chem. 2005 Apr 8;280(14):13913-20. Epub 2005 Jan 27. PMID:15677459 doi:http://dx.doi.org/10.1074/jbc.M409179200
↑ Piechotta A, Parthier C, Kleinschmidt M, Gnoth K, Pillot T, Lues I, Demuth HU, Schilling S, Rahfeld JU, Stubbs MT. Structural and functional analyses of pyroglutamate-amyloid-beta-specific antibodies as a basis for Alzheimer immunotherapy. J Biol Chem. 2017 Jul 28;292(30):12713-12724. doi: 10.1074/jbc.M117.777839. Epub , 2017 Jun 16. PMID:28623233 doi:http://dx.doi.org/10.1074/jbc.M117.777839

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5myk"

Categories: Large Structures | Mus musculus | Parthier C | Piechotta A | Stubbs MT

@@ Line 3: / Line 3: @@
 <StructureSection load='5myk' size='340' side='right'caption='[[5myk]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5myk]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MYK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5MYK FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5myk]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MYK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5MYK FirstGlance]. <br>
-</td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PCA:PYROGLUTAMIC+ACID'>PCA</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.6&#8491;</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5myk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5myk OCA], [http://pdbe.org/5myk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5myk RCSB], [http://www.ebi.ac.uk/pdbsum/5myk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5myk ProSAT]</span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PCA:PYROGLUTAMIC+ACID'>PCA</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5myk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5myk OCA], [https://pdbe.org/5myk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5myk RCSB], [https://www.ebi.ac.uk/pdbsum/5myk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5myk ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/A4_MOUSE A4_MOUSE]] Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis. Involved in cell mobility and transcription regulation through protein-protein interactions. Can promote transcription activation through binding to APBB1-KAT5 and inhibit 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. May be involved in copper homeostasis/oxidative stress through copper ion reduction. Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV (By similarity). The splice isoforms that contain the BPTI domain possess protease inhibitor activity. Induces a AGER-dependent pathway that involves activation of p38 MAPK, resulting in internalization of amyloid-beta peptide and leading to mitochondrial dysfunction in cultured cortical neurons (By similarity). Provides Cu(2+) ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1.<ref>PMID:15677459</ref>   Beta-amyloid peptides are lipophilic metal chelators with metal-reducing activity. Binds transient metals such as copper, zinc and iron. Rat and mouse beta-amyloid peptides bind only weakly transient metals and have little reducing activity due to substitutions of transient metal chelating residues. Beta-APP42 may activate mononuclear phagocytes in the brain and elicit inflammatory responses. Promotes both tau aggregation and TPK II-mediated phosphorylation. Also bind GPC1 in lipid rafts (By similarity).<ref>PMID:15677459</ref>   The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis.<ref>PMID:15677459</ref>   N-APP binds TNFRSF21 triggering caspase activation and degeneration of both neuronal cell bodies (via caspase-3) and axons (via caspase-6) (By similarity).<ref>PMID:15677459</ref>
+[https://www.uniprot.org/uniprot/A4_MOUSE A4_MOUSE] Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis. Involved in cell mobility and transcription regulation through protein-protein interactions. Can promote transcription activation through binding to APBB1-KAT5 and inhibit 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. May be involved in copper homeostasis/oxidative stress through copper ion reduction. Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV (By similarity). The splice isoforms that contain the BPTI domain possess protease inhibitor activity. Induces a AGER-dependent pathway that involves activation of p38 MAPK, resulting in internalization of amyloid-beta peptide and leading to mitochondrial dysfunction in cultured cortical neurons (By similarity). Provides Cu(2+) ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1.<ref>PMID:15677459</ref>   Beta-amyloid peptides are lipophilic metal chelators with metal-reducing activity. Binds transient metals such as copper, zinc and iron. Rat and mouse beta-amyloid peptides bind only weakly transient metals and have little reducing activity due to substitutions of transient metal chelating residues. Beta-APP42 may activate mononuclear phagocytes in the brain and elicit inflammatory responses. Promotes both tau aggregation and TPK II-mediated phosphorylation. Also bind GPC1 in lipid rafts (By similarity).<ref>PMID:15677459</ref>   The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis.<ref>PMID:15677459</ref>   N-APP binds TNFRSF21 triggering caspase activation and degeneration of both neuronal cell bodies (via caspase-3) and axons (via caspase-6) (By similarity).<ref>PMID:15677459</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 23: / Line 24: @@
 </StructureSection>
 [[Category: Large Structures]]
-[[Category: Lk3 transgenic mice]]
+[[Category: Mus musculus]]
-[[Category: Parthier, C]]
+[[Category: Parthier C]]
-[[Category: Piechotta, A]]
+[[Category: Piechotta A]]
-[[Category: Stubbs, M T]]
+[[Category: Stubbs MT]]
-[[Category: Alzheimer's disease]]
-[[Category: Fibrillation]]
-[[Category: Immune system]]
-[[Category: Monoclonal antibody]]
-[[Category: Pyroglutamate abeta]]

5myk

From Proteopedia

Current revision

Structure of Pyroglutamate-Abeta-specific Fab c#17 in complex with murine Abeta-pE3-18PEGb

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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