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Sökning: onr:"swepub:oai:DiVA.org:su-213415" > Molecular Structure...

LIBRIS Formathandbok  (Information om MARC21)
FältnamnIndikatorerMetadata
00004215naa a2200517 4500
001oai:DiVA.org:su-213415
003SwePub
008230104s2022 | |||||||||||000 ||eng|
009oai:prod.swepub.kib.ki.se:236465548
0247 a https://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-2134152 URI
0247 a https://doi.org/10.1021/jacsau.2c004382 DOI
0247 a http://kipublications.ki.se/Default.aspx?queryparsed=id:2364655482 URI
040 a (SwePub)sud (SwePub)ki
041 a engb eng
042 9 SwePub
072 7a ref2 swepub-contenttype
072 7a art2 swepub-publicationtype
1001 a Abelein, Axelu Karolinska Institutet4 aut
2451 0a Molecular Structure of Cu(II)-Bound Amyloid-β Monomer Implicated in Inhibition of Peptide Self-Assembly in Alzheimer’s Disease
264 c 2022-11-11
264 1b American Chemical Society (ACS),c 2022
338 a print2 rdacarrier
520 a Metal ions, such as copper and zinc ions, have been shown to strongly modulate the self-assembly of the amyloid-β (Aβ) peptide into insoluble fibrils, and elevated concentrations of metal ions have been found in amyloid plaques of Alzheimer’s patients. Among the physiological transition metal ions, Cu(II) ions play an outstanding role since they can trigger production of neurotoxic reactive oxygen species. In contrast, structural insights into Cu(II) coordination of Aβ have been challenging due to the paramagnetic nature of Cu(II). Here, we employed specifically tailored paramagnetic NMR experiments to determine NMR structures of Cu(II) bound to monomeric Aβ. We found that monomeric Aβ binds Cu(II) in the N-terminus and combined with molecular dynamics simulations, we could identify two prevalent coordination modes of Cu(II). For these, we report here the NMR structures of the Cu(II)–bound Aβ complex, exhibiting heavy backbone RMSD values of 1.9 and 2.1 Å, respectively. Further, applying aggregation kinetics assays, we identified the specific effect of Cu(II) binding on the Aβ nucleation process. Our results show that Cu(II) efficiently retards Aβ fibrillization by predominately reducing the rate of fibril-end elongation at substoichiometric ratios. A detailed kinetic analysis suggests that this specific effect results in enhanced Aβ oligomer generation promoted by Cu(II). These results can quantitatively be understood by Cu(II) interaction with the Aβ monomer, forming an aggregation inert complex. In fact, this mechanism is strikingly similar to other transition metal ions, suggesting a common mechanism of action of retarding Aβ self-assembly, where the metal ion binding to monomeric Aβ is a key determinant. 
650 7a NATURVETENSKAPx Kemi0 (SwePub)1042 hsv//swe
650 7a NATURAL SCIENCESx Chemical Sciences0 (SwePub)1042 hsv//eng
650 7a NATURVETENSKAPx Biologi0 (SwePub)1062 hsv//swe
650 7a NATURAL SCIENCESx Biological Sciences0 (SwePub)1062 hsv//eng
650 7a MEDICIN OCH HÄLSOVETENSKAPx Medicinska och farmaceutiska grundvetenskaperx Neurovetenskaper0 (SwePub)301052 hsv//swe
650 7a MEDICAL AND HEALTH SCIENCESx Basic Medicinex Neurosciences0 (SwePub)301052 hsv//eng
653 a amyloid-β peptide
653 a Alzheimer’s disease
653 a copper ion
653 a paramagnetic NMR
653 a aggregation kinetics
7001 a Ciofi-Baffoni, Simone4 aut
7001 a Mörman, Cecilia,d 1988-u Stockholms universitet,Institutionen för biokemi och biofysik,Karolinska Institutet, Sweden4 aut0 (Swepub:su)cewa0744
7001 a Kumar, Rakeshu Karolinska Institutet4 aut
7001 a Giachetti, Andrea4 aut
7001 a Piccioli, Mario4 aut
7001 a Biverstål, Henriku Karolinska Institutet4 aut
7102 a Karolinska Institutetb Institutionen för biokemi och biofysik4 org
7730 t JACS Aud : American Chemical Society (ACS)g 2:11, s. 2571-2584q 2:11<2571-2584x 2691-3704
8564 u https://doi.org/10.1021/jacsau.2c00438y Fulltext
8564 8u https://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-213415
8564 8u https://doi.org/10.1021/jacsau.2c00438
8564 8u http://kipublications.ki.se/Default.aspx?queryparsed=id:236465548

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