OCA at 05:38, 31 May 2023

2023-05-31T05:38:58Z

←Older revision		Revision as of 05:38, 31 May 2023
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-	'''Unreleased structure'''

-	The entry ~~8bfb~~ is ~~ON HOLD until Paper~~ Publication	+	==Sarkosyl-extracted AppNL-G-F Abeta42 fibril structure (Methoxy-X04-labelled mice)==
		+	<StructureSection load='8bfb' size='340' side='right'caption='[[8bfb]], [[Resolution\|resolution]] 3.20Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[8bfb]] is a 10 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=8BFB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8BFB FirstGlance]. <br>
		+	</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=8bfb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8bfb OCA], [https://pdbe.org/8bfb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8bfb RCSB], [https://www.ebi.ac.uk/pdbsum/8bfb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8bfb ProSAT]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[https://www.uniprot.org/uniprot/A4_HUMAN A4_HUMAN] Defects in APP are the cause of Alzheimer disease type 1 (AD1) [MIM:[https://omim.org/entry/104300 104300]. AD1 is a familial early-onset form of Alzheimer disease. It can be associated with cerebral amyloid angiopathy. Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituent of these plaques is the neurotoxic amyloid-beta-APP 40-42 peptide (s), derived proteolytically from the transmembrane precursor protein APP by sequential secretase processing. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products such as C31 derived from APP, are also implicated in neuronal death.<ref>PMID:8476439</ref> <ref>PMID:15201367</ref> <ref>PMID:1671712</ref> <ref>PMID:1908231</ref> <ref>PMID:1678058</ref> <ref>PMID:1944558</ref> <ref>PMID:1925564</ref> <ref>PMID:1415269</ref> <ref>PMID:1303239</ref> <ref>PMID:1302033</ref> <ref>PMID:1303275</ref> <ref>PMID:8267572</ref> <ref>PMID:8290042</ref> <ref>PMID:8577393</ref> <ref>PMID:9328472</ref> <ref>PMID:9754958</ref> <ref>PMID:10097173</ref> <ref>PMID:10631141</ref> <ref>PMID:10665499</ref> <ref>PMID:10867787</ref> <ref>PMID:11063718</ref> <ref>PMID:11311152</ref> <ref>PMID:11528419</ref> <ref>PMID:12034808</ref> <ref>PMID:15365148</ref> <ref>PMID:15668448</ref> Defects in APP are the cause of cerebral amyloid angiopathy APP-related (CAA-APP) [MIM:[https://omim.org/entry/605714 605714]. A hereditary localized amyloidosis due to amyloid-beta A4 peptide(s) deposition in the cerebral vessels. The principal clinical characteristics are recurrent cerebral and cerebellar hemorrhages, recurrent strokes, cerebral ischemia, cerebral infarction, and progressive mental deterioration. Patients develop cerebral hemorrhage because of the severe cerebral amyloid angiopathy. Parenchymal amyloid deposits are rare and largely in the form of pre-amyloid lesions or diffuse plaque-like structures. They are Congo red negative and lack the dense amyloid cores commonly present in Alzheimer disease. Some affected individuals manifest progressive aphasic dementia, leukoencephalopathy, and occipital calcifications.<ref>PMID:10821838</ref> <ref>PMID:2111584</ref> <ref>PMID:11409420</ref> <ref>PMID:12654973</ref> <ref>PMID:16178030</ref>
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/A4_HUMAN A4_HUMAN] 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 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 Cu(2+)-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. 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. 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:9168929</ref> <ref>PMID:11544248</ref> <ref>PMID:11943163</ref> <ref>PMID:19225519</ref> <ref>PMID:19901339</ref> Beta-amyloid peptides are lipophilic metal chelators with metal-reducing activity. Bind transient metals such as copper, zinc and iron. In vitro, can reduce Cu(2+) and Fe(3+) to Cu(+) and Fe(2+), 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 Also bind GPC1 in lipid rafts.<ref>PMID:9168929</ref> <ref>PMID:11544248</ref> <ref>PMID:11943163</ref> <ref>PMID:19225519</ref> <ref>PMID:19901339</ref> Appicans elicit adhesion of neural cells to the extracellular matrix and may regulate neurite outgrowth in the brain (By similarity).<ref>PMID:9168929</ref> <ref>PMID:11544248</ref> <ref>PMID:11943163</ref> <ref>PMID:19225519</ref> <ref>PMID:19901339</ref> The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis.<ref>PMID:9168929</ref> <ref>PMID:11544248</ref> <ref>PMID:11943163</ref> <ref>PMID:19225519</ref> <ref>PMID:19901339</ref> N-APP binds TNFRSF21 triggering caspase activation and degeneration of both neuronal cell bodies (via caspase-3) and axons (via caspase-6).<ref>PMID:9168929</ref> <ref>PMID:11544248</ref> <ref>PMID:11943163</ref> <ref>PMID:19225519</ref> <ref>PMID:19901339</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Amyloid plaques composed of Abeta fibrils are a hallmark of Alzheimer's disease (AD). However, the molecular architecture of amyloid plaques in the context of fresh mammalian brain tissue is unknown. Here, using cryogenic correlated light and electron tomography we report the in situ molecular architecture of Abeta fibrils in the App(NL-G-F) familial AD mouse model containing the Arctic mutation and an atomic model of ex vivo purified Arctic Abeta fibrils. We show that in-tissue Abeta fibrils are arranged in a lattice or parallel bundles, and are interdigitated by subcellular compartments, extracellular vesicles, extracellular droplets and extracellular multilamellar bodies. The Arctic Abeta fibril differs significantly from an earlier App(NL-F) fibril structure, indicating a striking effect of the Arctic mutation. These structural data also revealed an ensemble of additional fibrillar species, including thin protofilament-like rods and branched fibrils. Together, these results provide a structural model for the dense network architecture that characterises beta-amyloid plaque pathology.

-	~~Authors~~:	+	The in-tissue molecular architecture of beta-amyloid pathology in the mammalian brain.,Leistner C, Wilkinson M, Burgess A, Lovatt M, Goodbody S, Xu Y, Deuchars S, Radford SE, Ranson NA, Frank RAW Nat Commun. 2023 May 17;14(1):2833. doi: 10.1038/s41467-023-38495-5. PMID:37198197<ref>PMID:37198197</ref>

-	~~Description~~:	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
		+	<div class="pdbe-citations 8bfb" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Mus musculus]]
		+	[[Category: Burgess A]]
		+	[[Category: Deuchars S]]
		+	[[Category: Frank RAW]]
		+	[[Category: Goodfellow S]]
		+	[[Category: Leistner C]]
		+	[[Category: Radford SE]]
		+	[[Category: Ranson NA]]
		+	[[Category: Wilkinson M]]

OCA at 05:55, 21 December 2022

2022-12-21T05:55:54Z

←Older revision		Revision as of 05:55, 21 December 2022
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 8bfb is ON HOLD	+	The entry 8bfb is ON HOLD until Paper Publication

	Authors:		Authors:

OCA: Protected "8bfb" [edit=sysop:move=sysop]

2022-11-03T05:11:14Z

Protected "8bfb" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:11, 3 November 2022

OCA: New page: '''Unreleased structure''' The entry 8bfb is ON HOLD Authors: Description: Category: Unreleased Structures

2022-11-03T05:11:12Z

New page: '''Unreleased structure''' The entry 8bfb is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 8bfb is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]

8bfb - Revision history

OCA at 05:38, 31 May 2023

OCA at 05:55, 21 December 2022

OCA: Protected "8bfb" [edit=sysop:move=sysop]

OCA: New page: '''Unreleased structure''' The entry 8bfb is ON HOLD Authors: Description: Category: Unreleased Structures