Abstract
Apolipoprotein A-I (apoA-I) is the major protein constituent of high density lipoprotein (HDL) and plays a central role in phospholipid and cholesterol metabolism. This 243-residue long protein is remarkably flexible and assumes numerous lipid-dependent conformations. Consequently, definitive structural determination of lipid-free apoA-I in solution has been difficult. Using electron paramagnetic spectroscopy of site-directed spin labels in the N-terminal domain of apoA-I (residues 1-98) we have mapped a mixture of secondary structural elements, the composition of which is consistent with findings from other in-solution methods. Based on side chain mobility and their accessibility to polar and non-polar spin relaxers, the precise location of secondary elements for amino acids 14-98 was determined for both lipid-free and lipid-bound apoA-I. Based on intermolecular dipolar coupling at positions 26, 44, and 64, these secondary structural elements were arranged into a tertiary fold to generate a structural model for lipid-free apoA-I in solution.
Highlights
High density lipoprotein (HDL)3 plays a central role in lipid metabolism as a principal facilitator of reverse cholesterol transport, a process wherein cholesterol is mobilized from peripheral tissues and delivered to the liver and steroidogenic organs
Using electron paramagnetic spectroscopy of site-directed spin labels in the N-terminal domain of Apolipoprotein A-I (apoA-I) we have mapped a mixture of secondary structural elements, the composition of which is consistent with findings from other insolution methods
ApoA-I is a prominent member of the exchangeable apolipoprotein class of proteins, and HDL derives a large portion of its functionality from the ability of apoA-I to sequester phospholipid and cholesterol and functionally interact with plasma enzymes and cellular receptors
Summary
High density lipoprotein (HDL)3 plays a central role in lipid metabolism as a principal facilitator of reverse cholesterol transport, a process wherein cholesterol is mobilized from peripheral tissues and delivered to the liver and steroidogenic organs. Using electron paramagnetic spectroscopy of site-directed spin labels in the N-terminal domain of apoA-I (residues 1–98) we have mapped a mixture of secondary structural elements, the composition of which is consistent with findings from other insolution methods.
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