OCA at 07:25, 22 March 2023

OCA — Wed, 22 Mar 2023 07:25:14 GMT

←Older revision		Revision as of 07:25, 22 March 2023
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-	'''Unreleased structure'''

-	The entry ~~8ezd~~ is ~~ON HOLD until Paper~~ Publication	+	==Brain-derived 42-residue amyloid-beta fibril type A==
		+	<StructureSection load='8ezd' size='340' side='right'caption='[[8ezd]], [[Resolution\|resolution]] 2.83Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[8ezd]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8EZD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8EZD 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=8ezd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8ezd OCA], [https://pdbe.org/8ezd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8ezd RCSB], [https://www.ebi.ac.uk/pdbsum/8ezd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8ezd 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 ==
		+	Fibrils formed by the 42-residue amyloid-beta peptide (Abeta42), a main component of amyloid deposits in Alzheimer's disease (AD), are known to be polymorphic, i.e., to contain multiple possible molecular structures. Previous studies of Abeta42 fibrils, including fibrils prepared entirely in vitro or extracted from brain tissue and using solid-state NMR (ssNMR) or cryogenic electron microscopy (cryo-EM) methods, have found polymorphs with differences in amino acid sidechain orientations, lengths of structurally ordered segments, and contacts between cross-beta subunit pairs within a single filament. Despite these differences, Abeta42 molecules adopt a common S-shaped conformation in all previously described high-resolution Abeta42 fibril structures. Here we report two cryo-EM-based structures of Abeta42 fibrils that are qualitatively different, in samples derived from AD brain tissue by seeded growth. In type A fibrils, residues 12 to 42 adopt a nu-shaped conformation, with both intra-subunit and intersubunit hydrophobic contacts to form a compact core. In type B fibrils, residues 2 to 42 adopt an upsilon-shaped conformation, with only intersubunit contacts and internal pores. Type A and type B fibrils have opposite helical handedness. Cryo-EM density maps and molecular dynamics simulations indicate intersubunit K16-A42 salt bridges in type B fibrils and partially occupied K28-A42 salt bridges in type A fibrils. The coexistence of two predominant polymorphs, with differences in N-terminal dynamics, is supported by ssNMR data, as is faithful propagation of structures from first-generation to second-generation brain-seeded Abeta42 fibril samples. These results demonstrate that Abeta42 fibrils can exhibit a greater range of structural variations than seen in previous studies.

-	~~Authors: Tycko, R~~., Lee, M., Yau, Y.-M., ~~Louis, J~~.M.	+	Structures of brain-derived 42-residue amyloid-beta fibril polymorphs with unusual molecular conformations and intermolecular interactions.,Lee M, Yau WM, Louis JM, Tycko R Proc Natl Acad Sci U S A. 2023 Mar 14;120(11):e2218831120. doi: , 10.1073/pnas.2218831120. Epub 2023 Mar 9. PMID:36893281<ref>PMID:36893281</ref>

-	~~Description: Brain~~-~~derived 42~~-~~residue amyloid-beta fibril type A~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
-	[[Category: ~~Tycko, R~~]]	+	<div class="pdbe-citations 8ezd" style="background-color:#fffaf0;"></div>
-	[[Category: ~~Yau, Y.-~~M]]	+	== References ==
-	[[Category: ~~Lee, M~~]]	+	<references/>
-	[[Category: ~~Louis, J.~~M]]	+	__TOC__
		+	</StructureSection>
		+	[[Category: Homo sapiens]]
		+	[[Category: Large Structures]]
		+	[[Category: Lee M]]
		+	[[Category: Louis JM]]
		+	[[Category: Tycko R]]
		+	[[Category: Yau Y-M]]

OCA at 05:29, 7 December 2022

OCA — Wed, 07 Dec 2022 05:29:18 GMT

←Older revision		Revision as of 05:29, 7 December 2022
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

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

	Authors: Tycko, R., Lee, M., Yau, Y.-M., Louis, J.M.		Authors: Tycko, R., Lee, M., Yau, Y.-M., Louis, J.M.

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

OCA — Wed, 09 Nov 2022 05:06:45 GMT

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

←Older revision

Revision as of 05:06, 9 November 2022

OCA: New page: '''Unreleased structure''' The entry 8ezd is ON HOLD Authors: Tycko, R., Lee, M., Yau, Y.-M., Louis, J.M. Description: Brain-derived 42-residue amyloid-beta fibril type A [[Category: U...

OCA — Wed, 09 Nov 2022 05:06:43 GMT

New page: '''Unreleased structure''' The entry 8ezd is ON HOLD Authors: Tycko, R., Lee, M., Yau, Y.-M., Louis, J.M. Description: Brain-derived 42-residue amyloid-beta fibril type A [[Category: U...

New page

'''Unreleased structure'''

The entry 8ezd is ON HOLD

Authors: Tycko, R., Lee, M., Yau, Y.-M., Louis, J.M.

Description: Brain-derived 42-residue amyloid-beta fibril type A
[[Category: Unreleased Structures]]
[[Category: Tycko, R]]
[[Category: Yau, Y.-M]]
[[Category: Lee, M]]
[[Category: Louis, J.M]]

8ezd - Revision history

OCA at 07:25, 22 March 2023

OCA at 05:29, 7 December 2022

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

OCA: New page: '''Unreleased structure''' The entry 8ezd is ON HOLD Authors: Tycko, R., Lee, M., Yau, Y.-M., Louis, J.M. Description: Brain-derived 42-residue amyloid-beta fibril type A [[Category: U...