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Despite the importance of apoE in these major human diseases, the fundamental questions of how apoE adjusts its structure upon binding to regulate its diverse functions remain unsolved. We report the NMR structure of apoE3, displaying a unique topology of three structural domains. The C-terminal domain presents a large exposed hydrophobic surface that likely initiates interactions with lipids, HSPG, and beta amyloid peptides. The unique topology precisely regulates apoE tertiary structure to permit only one possible conformational adaptation upon binding and provides a double security in preventing lipid-free and partially-lipidated apoE from premature binding to apoE receptors during receptor biogenesis. This topology further ensures the optimal receptor-binding activity by the fully lipidated apoE during lipoprotein transport in circulation and in the brain. These findings provide a structural framework for understanding the structural basis of the diverse functions of this important protein in human diseases.<\/jats:p>","DOI":"10.1073\/pnas.1106420108","type":"journal-article","created":{"date-parts":[[2011,8,22]],"date-time":"2011-08-22T23:09:01Z","timestamp":1314054541000},"page":"14813-14818","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":269,"title":["Topology of human apolipoprotein E3 uniquely regulates its diverse biological functions"],"prefix":"10.1073","volume":"108","author":[{"given":"Jianglei","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, School of Medicine, Wayne State University, Detroit, MI 48201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianqian","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, School of Medicine, Wayne State University, Detroit, MI 48201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianjun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, School of Medicine, Wayne State University, Detroit, MI 48201"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2011,8,22]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/S0065-3233(08)60642-7","article-title":"Apolipoprotein E: structure-function relationships","volume":"45","author":"Weisgraber KH","year":"1994","unstructured":"KH Weisgraber, Apolipoprotein E: structure-function relationships. 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