The Pathogenic A2V Mutant Exhibits Distinct Aggregation Kinetics, Metal Site Structure, and Metal Exchange of the Cu2+-A[beta] Complex
A prominent current hypothesis is that impaired metal ion homeostasis may contribute to Alzheimer's disease (AD). We elucidate the interaction of Cu2+ with wild-type (WT) A[beta]1-40 and the genetic variants A2T and A2V which display increasing pathogenicity as A2T
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| Veröffentlicht in: | Chemistry : a European journal 2017-10, Vol.23 (55), p.13591 |
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| creator | Somavarapu, Arun K Shen, Fei Teilum, Kaare Zhang, Jingdong Mossin, Susanne Thulstrup, Peter W Bjerrum, Morten J Tiwari, Manish K Szunyogh, Daniel Sotofte, Peter M Kepp, Kasper P Hemmingsen, Lars |
| description | A prominent current hypothesis is that impaired metal ion homeostasis may contribute to Alzheimer's disease (AD). We elucidate the interaction of Cu2+ with wild-type (WT) A[beta]1-40 and the genetic variants A2T and A2V which display increasing pathogenicity as A2T |
| doi_str_mv | 10.1002/chem.201703440 |
| format | Article |
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We elucidate the interaction of Cu2+ with wild-type (WT) A[beta]1-40 and the genetic variants A2T and A2V which display increasing pathogenicity as A2T<WT<A2V. Cu2+ significantly extends the lag phase in aggregation kinetics, in particular for the pathogenic A2V variant. Additionally, a rapid, initial, low intensity ThT response is observed, possibly reflecting formation of Cu2+ induced amorphous aggregates, as supported by atomic force microscopy (AFM) and circular dichroism (CD) spectroscopy, again most notably for the A2V variant. Electron paramagnetic resonance (EPR) spectroscopy gives pKa values for transition between two Cu2+ coordination geometries (componentI and II) of 7.4 (A2T), 7.9 (WT), and 8.4 (A2V), that is, componentI is stabilized at physiological pH in the order A2T<WT<A2V. 1HNMR relaxation exhibits the same trend for the non-coordinating aromatic residues (A2T<WT<A2V), and implies markedly faster inter-peptide Cu2+exchange for the A2V variant than for WT and A2T. We therefore hypothesize that componentI of the Cu-A[beta] complex is related to pathogenicity, accounting for both the pathogenic nature of the A2V variant and the protective nature of the A2T variant.]]></description><identifier>ISSN: 0947-6539</identifier><identifier>EISSN: 1521-3765</identifier><identifier>DOI: 10.1002/chem.201703440</identifier><language>eng</language><publisher>Weinheim: Wiley Subscription Services, Inc</publisher><subject>Agglomeration ; Alzheimer's disease ; Atomic force microscopy ; Atomic structure ; Cadmium ; Chemistry ; Circular dichroism ; Copper ; Dichroism ; Electron paramagnetic resonance ; Homeostasis ; Kinetics ; Lag phase ; Metals ; Microscopy ; Neurodegenerative diseases ; Pathogenicity ; Pathogens ; pH effects ; Spectroscopy ; Spectrum analysis</subject><ispartof>Chemistry : a European journal, 2017-10, Vol.23 (55), p.13591</ispartof><rights>2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids></links><search><creatorcontrib>Somavarapu, Arun K</creatorcontrib><creatorcontrib>Shen, Fei</creatorcontrib><creatorcontrib>Teilum, Kaare</creatorcontrib><creatorcontrib>Zhang, Jingdong</creatorcontrib><creatorcontrib>Mossin, Susanne</creatorcontrib><creatorcontrib>Thulstrup, Peter W</creatorcontrib><creatorcontrib>Bjerrum, Morten J</creatorcontrib><creatorcontrib>Tiwari, Manish K</creatorcontrib><creatorcontrib>Szunyogh, Daniel</creatorcontrib><creatorcontrib>Sotofte, Peter M</creatorcontrib><creatorcontrib>Kepp, Kasper P</creatorcontrib><creatorcontrib>Hemmingsen, Lars</creatorcontrib><title>The Pathogenic A2V Mutant Exhibits Distinct Aggregation Kinetics, Metal Site Structure, and Metal Exchange of the Cu2+-A[beta] Complex</title><title>Chemistry : a European journal</title><description><![CDATA[A prominent current hypothesis is that impaired metal ion homeostasis may contribute to Alzheimer's disease (AD). We elucidate the interaction of Cu2+ with wild-type (WT) A[beta]1-40 and the genetic variants A2T and A2V which display increasing pathogenicity as A2T<WT<A2V. Cu2+ significantly extends the lag phase in aggregation kinetics, in particular for the pathogenic A2V variant. Additionally, a rapid, initial, low intensity ThT response is observed, possibly reflecting formation of Cu2+ induced amorphous aggregates, as supported by atomic force microscopy (AFM) and circular dichroism (CD) spectroscopy, again most notably for the A2V variant. Electron paramagnetic resonance (EPR) spectroscopy gives pKa values for transition between two Cu2+ coordination geometries (componentI and II) of 7.4 (A2T), 7.9 (WT), and 8.4 (A2V), that is, componentI is stabilized at physiological pH in the order A2T<WT<A2V. 1HNMR relaxation exhibits the same trend for the non-coordinating aromatic residues (A2T<WT<A2V), and implies markedly faster inter-peptide Cu2+exchange for the A2V variant than for WT and A2T. We therefore hypothesize that componentI of the Cu-A[beta] complex is related to pathogenicity, accounting for both the pathogenic nature of the A2V variant and the protective nature of the A2T variant.]]></description><subject>Agglomeration</subject><subject>Alzheimer's disease</subject><subject>Atomic force microscopy</subject><subject>Atomic structure</subject><subject>Cadmium</subject><subject>Chemistry</subject><subject>Circular dichroism</subject><subject>Copper</subject><subject>Dichroism</subject><subject>Electron paramagnetic resonance</subject><subject>Homeostasis</subject><subject>Kinetics</subject><subject>Lag phase</subject><subject>Metals</subject><subject>Microscopy</subject><subject>Neurodegenerative diseases</subject><subject>Pathogenicity</subject><subject>Pathogens</subject><subject>pH effects</subject><subject>Spectroscopy</subject><subject>Spectrum analysis</subject><issn>0947-6539</issn><issn>1521-3765</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><recordid>eNqNzU9LwzAYx_EgCtY_V88PeHSdSZO25FjqhiADYcOLyMjiszajS2fzBPoKfN32sBfg6Xf4_ODL2IPgc8F59mxbPM4zLkouleIXLBF5JlJZFvklS7hWZVrkUl-zmxAOnHNdSJmw302L8G6o7Rv0zkKVfcAqkvEEi7F1O0cBXlwg5y1B1TQDNoZc7-HNeSRnwwxWSKaDtSOENQ3RUhxwBsZ_n2Ux2tb4BqHfA021OmZPafW5m_AL6v546nC8Y1d70wW8P-8te1wuNvVrehr6n4iBtoc-Dn6irdCqEErpQsv_vf4A4zpXUg</recordid><startdate>20171004</startdate><enddate>20171004</enddate><creator>Somavarapu, Arun K</creator><creator>Shen, Fei</creator><creator>Teilum, Kaare</creator><creator>Zhang, Jingdong</creator><creator>Mossin, Susanne</creator><creator>Thulstrup, Peter W</creator><creator>Bjerrum, Morten J</creator><creator>Tiwari, Manish K</creator><creator>Szunyogh, Daniel</creator><creator>Sotofte, Peter M</creator><creator>Kepp, Kasper P</creator><creator>Hemmingsen, Lars</creator><general>Wiley Subscription Services, Inc</general><scope>7SR</scope><scope>8BQ</scope><scope>8FD</scope><scope>JG9</scope><scope>K9.</scope></search><sort><creationdate>20171004</creationdate><title>The Pathogenic A2V Mutant Exhibits Distinct Aggregation Kinetics, Metal Site Structure, and Metal Exchange of the Cu2+-A[beta] Complex</title><author>Somavarapu, Arun K ; Shen, Fei ; Teilum, Kaare ; Zhang, Jingdong ; Mossin, Susanne ; Thulstrup, Peter W ; Bjerrum, Morten J ; Tiwari, Manish K ; Szunyogh, Daniel ; Sotofte, Peter M ; Kepp, Kasper P ; Hemmingsen, Lars</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-proquest_journals_19461449693</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Agglomeration</topic><topic>Alzheimer's disease</topic><topic>Atomic force microscopy</topic><topic>Atomic structure</topic><topic>Cadmium</topic><topic>Chemistry</topic><topic>Circular dichroism</topic><topic>Copper</topic><topic>Dichroism</topic><topic>Electron paramagnetic resonance</topic><topic>Homeostasis</topic><topic>Kinetics</topic><topic>Lag phase</topic><topic>Metals</topic><topic>Microscopy</topic><topic>Neurodegenerative diseases</topic><topic>Pathogenicity</topic><topic>Pathogens</topic><topic>pH effects</topic><topic>Spectroscopy</topic><topic>Spectrum analysis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Somavarapu, Arun K</creatorcontrib><creatorcontrib>Shen, Fei</creatorcontrib><creatorcontrib>Teilum, Kaare</creatorcontrib><creatorcontrib>Zhang, Jingdong</creatorcontrib><creatorcontrib>Mossin, Susanne</creatorcontrib><creatorcontrib>Thulstrup, Peter W</creatorcontrib><creatorcontrib>Bjerrum, Morten J</creatorcontrib><creatorcontrib>Tiwari, Manish K</creatorcontrib><creatorcontrib>Szunyogh, Daniel</creatorcontrib><creatorcontrib>Sotofte, Peter M</creatorcontrib><creatorcontrib>Kepp, Kasper P</creatorcontrib><creatorcontrib>Hemmingsen, Lars</creatorcontrib><collection>Engineered Materials Abstracts</collection><collection>METADEX</collection><collection>Technology Research Database</collection><collection>Materials Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><jtitle>Chemistry : a European journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Somavarapu, Arun K</au><au>Shen, Fei</au><au>Teilum, Kaare</au><au>Zhang, Jingdong</au><au>Mossin, Susanne</au><au>Thulstrup, Peter W</au><au>Bjerrum, Morten J</au><au>Tiwari, Manish K</au><au>Szunyogh, Daniel</au><au>Sotofte, Peter M</au><au>Kepp, Kasper P</au><au>Hemmingsen, Lars</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Pathogenic A2V Mutant Exhibits Distinct Aggregation Kinetics, Metal Site Structure, and Metal Exchange of the Cu2+-A[beta] Complex</atitle><jtitle>Chemistry : a European journal</jtitle><date>2017-10-04</date><risdate>2017</risdate><volume>23</volume><issue>55</issue><spage>13591</spage><pages>13591-</pages><issn>0947-6539</issn><eissn>1521-3765</eissn><abstract><![CDATA[A prominent current hypothesis is that impaired metal ion homeostasis may contribute to Alzheimer's disease (AD). We elucidate the interaction of Cu2+ with wild-type (WT) A[beta]1-40 and the genetic variants A2T and A2V which display increasing pathogenicity as A2T<WT<A2V. Cu2+ significantly extends the lag phase in aggregation kinetics, in particular for the pathogenic A2V variant. Additionally, a rapid, initial, low intensity ThT response is observed, possibly reflecting formation of Cu2+ induced amorphous aggregates, as supported by atomic force microscopy (AFM) and circular dichroism (CD) spectroscopy, again most notably for the A2V variant. Electron paramagnetic resonance (EPR) spectroscopy gives pKa values for transition between two Cu2+ coordination geometries (componentI and II) of 7.4 (A2T), 7.9 (WT), and 8.4 (A2V), that is, componentI is stabilized at physiological pH in the order A2T<WT<A2V. 1HNMR relaxation exhibits the same trend for the non-coordinating aromatic residues (A2T<WT<A2V), and implies markedly faster inter-peptide Cu2+exchange for the A2V variant than for WT and A2T. We therefore hypothesize that componentI of the Cu-A[beta] complex is related to pathogenicity, accounting for both the pathogenic nature of the A2V variant and the protective nature of the A2T variant.]]></abstract><cop>Weinheim</cop><pub>Wiley Subscription Services, Inc</pub><doi>10.1002/chem.201703440</doi></addata></record> |
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| subjects | Agglomeration Alzheimer's disease Atomic force microscopy Atomic structure Cadmium Chemistry Circular dichroism Copper Dichroism Electron paramagnetic resonance Homeostasis Kinetics Lag phase Metals Microscopy Neurodegenerative diseases Pathogenicity Pathogens pH effects Spectroscopy Spectrum analysis |
| title | The Pathogenic A2V Mutant Exhibits Distinct Aggregation Kinetics, Metal Site Structure, and Metal Exchange of the Cu2+-A[beta] Complex |
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