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Dissertation
The molecular properties of apoliprotein E: isoform structural stabilities and phospholipid interaction
Doctor of Philosophy (Ph.D.), Medical College of Pennsylvania and Hahnemann University
Apr 2002
DOI:
https://doi.org/10.17918/00009008
Abstract
We examined the effects of apolipoprotein E domain structure and polymorphism on the kinetics of solubilization (clearance) of dimyristoyl-phosphatidylcholine multilamellar vesicles. This second order reaction consisted of two simultaneous kinetic phases; it also exhibited saturable kinetics when the apolipoprotein concentration was increased at a constant lipid concentration. Rigid connections between [alpha]-helices in the four-helix bundle formed by the 22-kDa N-terminal domain of apoE reduced the reaction rate. In contrast, the more flexible interhelical connections in apo AI and the 10-kDa C-terminal domain of apoE promoted rapid solubilization of DMPC MLV. Full-length apoE3 reacted at about half the rate of the C-terminal domain alone. This decrease occurred because the hinge region probably decreased the interhelical flexibility of the 10-kDa domain and because both domains are conformationally restricted when covalently linked. Furthermore, the MLV surface affinities and reaction rates of the N-terminal domain fragments of the three common apoE isoforms tended to vary inversely with the stabilities of these fragments. These results confirm the importance of apoE's structure on the kinetics of lipid interaction. They suggest that flexibility in an apolipoprotein molecule increases the time-averaged surface area, thereby increasing the rate of phospholipid solubilization.
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Details
- Title
- The molecular properties of apoliprotein E
- Creators
- Mark Louis Segall
- Awarding Institution
- Medical College of Pennsylvania and Hahnemann University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Medical College of Pennsylvania and Hahnemann University; Philadelphia, Pennsylvania
- Number of pages
- xiii, 141 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- School of Medicine (1993-1996, 1998-2002); Medical College of Pennsylvania and Hahnemann University (1993-1996, 1998-2002)
- Other Identifier
- 991021888879604721