Influence of Domain Stability on the Properties of Human Apolipoprotein E3 and E4 and Mouse Apolipoprotein E
| العنوان: | Influence of Domain Stability on the Properties of Human Apolipoprotein E3 and E4 and Mouse Apolipoprotein E |
|---|---|
| المؤلفون: | David Nguyen, Sissel Lund-Katz, Padmaja Dhanasekaran, Hiroyuki Saito, Chiharu Mizuguchi, Mayu Watanabe, Michael C. Phillips, Margaret Nickel |
| المصدر: | Biochemistry |
| بيانات النشر: | American Chemical Society, 2014. |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | Apolipoprotein E, Gene isoform, Apolipoprotein E4, Apolipoprotein E3, Plasma protein binding, Biology, Lipoproteins, VLDL, Biochemistry, Article, Apolipoproteins E, 03 medical and health sciences, Mice, 0302 clinical medicine, Protein structure, Animals, Humans, Protein Isoforms, 030304 developmental biology, Helix bundle, 0303 health sciences, Protein Stability, Lipids, Protein Structure, Tertiary, Biophysics, lipids (amino acids, peptides, and proteins), Apolipoprotein C2, Dimyristoylphosphatidylcholine, 030217 neurology & neurosurgery, Triolein, Lipoprotein, Protein Binding |
| الوصف: | 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. |
| اللغة: | English |
| تدمد: | 1520-4995 0006-2960 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ff3d231c13c3e5fb1ba368dbf58d3e2eTest http://europepmc.org/articles/PMC4071092Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....ff3d231c13c3e5fb1ba368dbf58d3e2e |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15204995 00062960 |
|---|