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Here, we investigate the molecular mechanism of apoE\u2010A\u03b2 interactions by comparing the effects of the different domains of apoE on A\u03b2. The kinetics of aggregation of A\u03b21\u201042 are delayed dramatically in the presence of substoichiometric, nanomolar concentrations of N\u2010terminal fragment (<jats:styled-content style=\"fixed-case\">NTF<\/jats:styled-content>), C\u2010terminal fragment (<jats:styled-content style=\"fixed-case\">CTF<\/jats:styled-content>) and full\u2010length apoE both in lipid\u2010free and in lipidated forms. However, interactions between apoE and A\u03b2 as measured by intermolecular F\u00f6rster resonance energy transfer (<jats:styled-content style=\"fixed-case\">FRET<\/jats:styled-content>) analysis were found to be minimal at t\u00a0=\u00a00 but to increase in a time\u2010dependent manner. Thus, apoE must interact with one or more \u2018intermediates\u2019 rather than the monomers of A\u03b2. Kinetics of <jats:styled-content style=\"fixed-case\">FRET<\/jats:styled-content> between full\u2010length apoE4 labelled with <jats:styled-content style=\"fixed-case\">EDANS<\/jats:styled-content> at position 62 or 139 or 210 or 247 or 276, and tetramethylrhodamine\u2010labelled A\u03b2 (<jats:styled-content style=\"fixed-case\">TMR<\/jats:styled-content>\u2010A\u03b2), further support an involvement of all the three domains of apoE in the interactions. However, the above\u2010mentioned residues do not appear to form a single pocket in the 3\u2010dimensional structure of apoE. A competitive binding assay examining the effects of unlabelled fragments or full\u2010length apoE on the <jats:styled-content style=\"fixed-case\">FRET<\/jats:styled-content> between <jats:styled-content style=\"fixed-case\">EDANS<\/jats:styled-content>\u2010apoE and <jats:styled-content style=\"fixed-case\">TMR<\/jats:styled-content>\u2010A\u03b2 show that binding affinity of the full\u2010length apoE to A\u03b2 is much higher than that of the fragments. Furthermore, apoE4 is found to interact more strongly than apoE3. We hypothesize that high affinity of the apoE\u2010A\u03b2 interaction is attained due to multivalent binding mediated by multiple interactions between oligomeric A\u03b2 and full\u2010length apoE.<\/jats:p>","DOI":"10.1111\/febs.14988","type":"journal-article","created":{"date-parts":[[2019,7,9]],"date-time":"2019-07-09T15:39:34Z","timestamp":1562686774000},"page":"4737-4753","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["High\u2010affinity multivalent interactions between apolipoprotein E and the oligomers of amyloid\u2010\u03b2"],"prefix":"10.1111","volume":"286","author":[{"given":"Shamasree","family":"Ghosh","sequence":"first","affiliation":[{"name":"Tata Institute of Fundamental Research Hyderabad Hyderabad India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timir Baran","family":"Sil","sequence":"additional","affiliation":[{"name":"Tata Institute of Fundamental Research Hyderabad 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