Role of Conserved Proline Residues in Human Apolipoprotein A-IV Structure and Function.

The Journal of Biological Chemistry
Xiaodi DengThomas B Thompson

Abstract

Apolipoprotein (apo)A-IV is a lipid emulsifying protein linked to a range of protective roles in obesity, diabetes, and cardiovascular disease. It exists in several states in plasma including lipid-bound in HDL and chylomicrons and as monomeric and dimeric lipid-free/poor forms. Our recent x-ray crystal structure of the central domain of apoA-IV shows that it adopts an elongated helical structure that dimerizes via two long reciprocating helices. A striking feature is the alignment of conserved proline residues across the dimer interface. We speculated that this plays important roles in the structure of the lipid-free protein and its ability to bind lipid. Here we show that the systematic conversion of these prolines to alanine increased the thermodynamic stability of apoA-IV and its propensity to oligomerize. Despite the structural stabilization, we noted an increase in the ability to bind and reorganize lipids and to promote cholesterol efflux from cells. The novel properties of these mutants allowed us to isolate the first trimeric form of an exchangeable apolipoprotein and characterize it by small-angle x-ray scattering and chemical cross-linking. The results suggest that the reciprocating helix interaction is a common feat...Continue Reading

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Citations

Feb 13, 2016·Clinica Chimica Acta; International Journal of Clinical Chemistry·Josep JulveFrancisco Blanco-Vaca
Oct 11, 2015·Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology·J Roman-PadillaM Manchado
Jun 22, 2016·Human Vaccines & Immunotherapeutics·Yizhi ZhangBin Wang
Jan 26, 2021·Frontiers in Cell and Developmental Biology·Ting LiuHua Tang

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