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Abstract
Apolipoprotein (apoA-IV) is a 376-residue exchangeable apolipoprotein that may play a number of important roles in lipid metabolism, including chylomicron assembly, reverse cholesterol transport, and appetite regulation. In vivo, apoA-IV exists in both lipid-poor and lipid-associated forms, and the balance between these states may determine its function. We examined the structural elements that modulate apoA-IV lipid binding by producing a series of deletion mutants and determining their ability to interact with phospholipid liposomes. We found that the deletion of residues 333-343 strongly increased the lipid association rate versus native apoA-IV. Additional mutagenesis revealed that two phenylalanine residues at positions 334 and 335 mediated this lipid binding inhibitory effect. We also observed that residues 11-20 in the N terminus were required for the enhanced lipid affinity induced by deletion of the C-terminal sequence. We propose a structural model in which these sequences can modulate the conformation and lipid affinity of apoA-IV.
Highlights
Human apolipoprotein3 A-IV is a 46-kDa glycoprotein that is the largest member of the exchangeable apolipoprotein family
As the DMPC assay measures the end result of a complex process that involves both an initial apolipoprotein-lipid interaction and a subsequent lipid reorganization, we examined the lipid affinity of WT and ⌬333–376 apoA-IV using oil drop tensiometry (25)
It is well established that apoA-IV binds to lipid with much lower affinity than other members of the exchangeable apolipoprotein family (21, 23)
Summary
Human apolipoprotein (apo) A-IV is a 46-kDa glycoprotein that is the largest member of the exchangeable apolipoprotein family. It is synthesized by enterocytes of the small intestine in response to lipid absorption and is secreted into circulation on the surface of chylomicrons. A distinct feature of the primary sequences of the exchangeable apolipoproteins is a variable number of 22-residue amphipathic ␣-helical repeats, which likely confer the ability to bind to the surface of lipoprotein particles (8). Lipid-free forms of apoA-I and apoE have been shown to exhibit a compartmentalized architecture characterized by a well organized N-terminal domain and a relatively unstable C-terminal domain (11– 13) that contains lipid binding sequences. The goal of the present study was to identify the sequence(s) in the C-terminal region responsible for this lipid binding inhibitory effect
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