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Influence of Domain Stability on the Properties of Human Apolipoprotein E3 and E4 and Mouse Apolipoprotein E

[Image: see text] The human apolipoprotein (apo) E4 isoform, which differs from wild-type apoE3 by the single amino acid substitution C112R, is associated with elevated risk of cardiovascular and Alzheimer’s diseases, but the molecular basis for this variation between isoforms is not understood. Hum...

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Autores principales: Nguyen, David, Dhanasekaran, Padmaja, Nickel, Margaret, Mizuguchi, Chiharu, Watanabe, Mayu, Saito, Hiroyuki, Phillips, Michael C., Lund-Katz, Sissel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2014
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4071092/
https://www.ncbi.nlm.nih.gov/pubmed/24871385
http://dx.doi.org/10.1021/bi500340z
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author Nguyen, David
Dhanasekaran, Padmaja
Nickel, Margaret
Mizuguchi, Chiharu
Watanabe, Mayu
Saito, Hiroyuki
Phillips, Michael C.
Lund-Katz, Sissel
author_facet Nguyen, David
Dhanasekaran, Padmaja
Nickel, Margaret
Mizuguchi, Chiharu
Watanabe, Mayu
Saito, Hiroyuki
Phillips, Michael C.
Lund-Katz, Sissel
author_sort Nguyen, David
collection PubMed
description [Image: see text] The human apolipoprotein (apo) E4 isoform, which differs from wild-type apoE3 by the single amino acid substitution C112R, is associated with elevated risk of cardiovascular and Alzheimer’s diseases, but the molecular basis for this variation between isoforms is not understood. Human apoE is a two-domain protein comprising an N-terminal helix bundle and a separately folded C-terminal region. Here, we examine the concept that the ability of the protein to bind to lipid surfaces is influenced by the stability (or readiness to unfold) of these domains. The lipid-free structures and abilities to bind to lipid and lipoprotein particles of a series of human and mouse apoE variants with varying domain stabilities and domain–domain interactions are compared. As assessed by urea denaturation, the two domains are more unstable in apoE4 than in apoE3. To distinguish the contributions of the destabilization of each domain to the greater lipid-binding ability of apoE4, the properties of the apoE4 R61T and E255A variants, which have the same helix bundle stabilities but altered C-terminal domain stabilities, are compared. In these cases, the effects on lipid-binding properties are relatively minor, indicating that the destabilization of the helix bundle domain is primarily responsible for the enhanced lipid-binding ability of apoE4. Unlike human apoE, mouse apoE behaves essentially as a single domain, and its lipid-binding characteristics are more similar to those of apoE4. Together, the results show that the overall stability of the entire apoE molecule exerts a major influence on its lipid- and lipoprotein-binding properties.
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spelling pubmed-40710922014-06-26 Influence of Domain Stability on the Properties of Human Apolipoprotein E3 and E4 and Mouse Apolipoprotein E Nguyen, David Dhanasekaran, Padmaja Nickel, Margaret Mizuguchi, Chiharu Watanabe, Mayu Saito, Hiroyuki Phillips, Michael C. Lund-Katz, Sissel Biochemistry [Image: see text] The human apolipoprotein (apo) E4 isoform, which differs from wild-type apoE3 by the single amino acid substitution C112R, is associated with elevated risk of cardiovascular and Alzheimer’s diseases, but the molecular basis for this variation between isoforms is not understood. Human apoE is a two-domain protein comprising an N-terminal helix bundle and a separately folded C-terminal region. Here, we examine the concept that the ability of the protein to bind to lipid surfaces is influenced by the stability (or readiness to unfold) of these domains. The lipid-free structures and abilities to bind to lipid and lipoprotein particles of a series of human and mouse apoE variants with varying domain stabilities and domain–domain interactions are compared. As assessed by urea denaturation, the two domains are more unstable in apoE4 than in apoE3. To distinguish the contributions of the destabilization of each domain to the greater lipid-binding ability of apoE4, the properties of the apoE4 R61T and E255A variants, which have the same helix bundle stabilities but altered C-terminal domain stabilities, are compared. In these cases, the effects on lipid-binding properties are relatively minor, indicating that the destabilization of the helix bundle domain is primarily responsible for the enhanced lipid-binding ability of apoE4. Unlike human apoE, mouse apoE behaves essentially as a single domain, and its lipid-binding characteristics are more similar to those of apoE4. Together, the results show that the overall stability of the entire apoE molecule exerts a major influence on its lipid- and lipoprotein-binding properties. American Chemical Society 2014-05-28 2014-06-24 /pmc/articles/PMC4071092/ /pubmed/24871385 http://dx.doi.org/10.1021/bi500340z Text en Copyright © 2014 American Chemical Society Terms of Use (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html)
spellingShingle Nguyen, David
Dhanasekaran, Padmaja
Nickel, Margaret
Mizuguchi, Chiharu
Watanabe, Mayu
Saito, Hiroyuki
Phillips, Michael C.
Lund-Katz, Sissel
Influence of Domain Stability on the Properties of Human Apolipoprotein E3 and E4 and Mouse Apolipoprotein E
title Influence of Domain Stability on the Properties of Human Apolipoprotein E3 and E4 and Mouse Apolipoprotein E
title_full Influence of Domain Stability on the Properties of Human Apolipoprotein E3 and E4 and Mouse Apolipoprotein E
title_fullStr Influence of Domain Stability on the Properties of Human Apolipoprotein E3 and E4 and Mouse Apolipoprotein E
title_full_unstemmed Influence of Domain Stability on the Properties of Human Apolipoprotein E3 and E4 and Mouse Apolipoprotein E
title_short Influence of Domain Stability on the Properties of Human Apolipoprotein E3 and E4 and Mouse Apolipoprotein E
title_sort influence of domain stability on the properties of human apolipoprotein e3 and e4 and mouse apolipoprotein e
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4071092/
https://www.ncbi.nlm.nih.gov/pubmed/24871385
http://dx.doi.org/10.1021/bi500340z
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