Abstract
The T347S polymorphism in the human apolipoprotein (apo) A-IV gene is present at high frequencies among all the world's populations. Carriers of a 347S allele exhibit faster clearance of triglyceride-rich lipoproteins, greater adiposity, and increased risk for developing atherosclerosis, which suggests that this conservative amino acid substitution alters the structure of apo A-IV. Herein we have used spectroscopic and surface chemistry techniques to examine the structure, stability, and interfacial properties of the apo A-IV 347S isoprotein. Circular dichroism spectroscopy revealed that the 347S isoprotein has similar alpha-helical structure but lower thermodynamic stability than the 347T isoprotein. Fluorescence spectroscopy found that the 347S isoprotein exhibits an enhanced tyrosine emission and reduced tyrosine-->tryptophan energy transfer, and second derivative UV absorption spectra noted increased tyrosine exposure, suggesting that the 347S isoprotein adopts a looser tertiary conformation. Surface chemistry studies found that although the 347S isoprotein bound rapidly to the lipid interface, it has a lower interfacial exclusion pressure and lower elastic modulus than the 347T isoprotein. Together, these observations establish that the T347S substitution alters the conformation of apo A-IV and lowers its interfacial activity-changes that could account for the effect of this polymorphism on postprandial lipid metabolism.
Highlights
The T347S polymorphism in the human apolipoprotein A-IV gene is present at high frequencies among all the world’s populations
Circular dichroism (CD) spectra of the apo A-IV isoproteins displayed mean residue ellipticity minima at 222 nm of 26,229 ± 849 deg·cm2·dmolϪ1 for apo A-IV 347S and 28,306 ± 2750 deg·cm2·dmolϪ1 for apo A-IV 347T (Fig. 2), corresponding to 76% and 77% ␣-helical structure, respectively
Van’t Hoff plots of the data (Fig. 3, inset) yielded thermodynamic stability parameters (Table 1): for apo A-IV 347S, the mean enthalpy of denaturation was 51.3 ± 2.8 kcal/ mol, and the mean entropy of unfolding was 159.4 ± 9.0 cal/mol°K; for apo A-IV 347T, the mean enthalpy of denaturation was 70.7 ± 1.4 kcal/mol, and the mean entropy of unfolding was 218.7 ± 4.2 cal/mol°K. These data suggest that the ordered structure of the apo A-IV 347S isoprotein is less stable than apo A-IV 347T
Summary
The T347S polymorphism in the human apolipoprotein (apo) A-IV gene is present at high frequencies among all the world’s populations. As tyrosine fluorescence in apo A-IV is suppressed by efficient energy transfer to the amino terminal tryptophan [27], this finding suggests that the average distance between the N-terminus and one or more tyrosine residues is greater in the 347S isoprotein.
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