Sökning: WFRF:(Abelein Axel) > Molecular Structure...
Fältnamn | Indikatorer | Metadata |
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000 | 04215naa a2200517 4500 | |
001 | oai:DiVA.org:su-213415 | |
003 | SwePub | |
008 | 230104s2022 | |||||||||||000 ||eng| | |
009 | oai:prod.swepub.kib.ki.se:236465548 | |
024 | 7 | a https://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-2134152 URI |
024 | 7 | a https://doi.org/10.1021/jacsau.2c004382 DOI |
024 | 7 | 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 | 7 | a ref2 swepub-contenttype |
072 | 7 | a art2 swepub-publicationtype |
100 | 1 | a Abelein, Axelu Karolinska Institutet4 aut |
245 | 1 0 | a 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 | 1 | b 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 | 7 | a NATURVETENSKAPx Kemi0 (SwePub)1042 hsv//swe |
650 | 7 | a NATURAL SCIENCESx Chemical Sciences0 (SwePub)1042 hsv//eng |
650 | 7 | a NATURVETENSKAPx Biologi0 (SwePub)1062 hsv//swe |
650 | 7 | a NATURAL SCIENCESx Biological Sciences0 (SwePub)1062 hsv//eng |
650 | 7 | a MEDICIN OCH HÄLSOVETENSKAPx Medicinska och farmaceutiska grundvetenskaperx Neurovetenskaper0 (SwePub)301052 hsv//swe |
650 | 7 | a 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 | |
700 | 1 | a Ciofi-Baffoni, Simone4 aut |
700 | 1 | a Mörman, Cecilia,d 1988-u Stockholms universitet,Institutionen för biokemi och biofysik,Karolinska Institutet, Sweden4 aut0 (Swepub:su)cewa0744 |
700 | 1 | a Kumar, Rakeshu Karolinska Institutet4 aut |
700 | 1 | a Giachetti, Andrea4 aut |
700 | 1 | a Piccioli, Mario4 aut |
700 | 1 | a Biverstål, Henriku Karolinska Institutet4 aut |
710 | 2 | a Karolinska Institutetb Institutionen för biokemi och biofysik4 org |
773 | 0 | t JACS Aud : American Chemical Society (ACS)g 2:11, s. 2571-2584q 2:11<2571-2584x 2691-3704 |
856 | 4 | u https://doi.org/10.1021/jacsau.2c00438y Fulltext |
856 | 4 8 | u https://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-213415 |
856 | 4 8 | u https://doi.org/10.1021/jacsau.2c00438 |
856 | 4 8 | u http://kipublications.ki.se/Default.aspx?queryparsed=id:236465548 |
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