Distinctive structure and interfacial activity of the human apolipoprotein A-IV 347S isoprotein.
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.
Weinberg
Richard B
RB
Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA. weinberg@wfubmc.edu
Cook
Victoria R
VR
D001054:Apolipoproteins A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002942:Circular Dichroism; D006801:Humans; D011110:Polymorphism, Genetic; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013050:Spectrometry, Fluorescence; D013816:Thermodynamics
D001054:Apolipoproteins A; D020033:Protein Isoforms; C022205:apolipoprotein A-IV