Human plasma apolipoproteins A-IV-0 and A-IV-3. Molecular basis for two rare variants of apolipoprotein A-IV-1.
Human apolipoprotein (apo) A-IV is a polymorphic plasma protein controlled by two codominant alleles at a single genetic locus. Thus far, five different isoproteins (apoA-IV-0 to apoA-IV-4) have been described in Caucasians. We have recently identified the nucleotide and amino acid substitutions that are the basis for the most common isoproteins, apoA-IV-1 and apoA-IV-2. In this report, the mutations producing the two rare isoproteins apoA-IV-0 and apoA-IV-3 are described. Analysis of the apoA-IV-0 allele revealed an insertion of 12 nucleotides in a carboxyl-terminal region, which is highly conserved among human, rat, and mouse A-IV apolipoproteins. This in-frame insertion of the 4 amino acids Glu-Gln-Gln-Gln between residues 361 and 362 of the mature protein produces the 1 charge unit more acidic apoA-IV-0 isoprotein (pI 4.92). In the apoA-IV-3 allele we identified a single G to A substitution that converts the glutamic acid (GAG) at position 230 of the mature protein to a lysine (AAG), thus adding 2 positive charge units to the apoA-IV-1 isoprotein (pI 4.97) and forming the more basic apoA-IV-3 isoprotein (pI 5.08). Comparison with the mouse and rat A-IV apolipoproteins revealed that this residue, located at position 4 of the 10th/11th amphiphilic alpha-helical repeat, is also highly conserved in evolution.
Lohse
P
P
Molecular Disease Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892.
Kindt
M R
MR
Rader
D J
DJ
Brewer
H B
HB
D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001054:Apolipoproteins A / Q000235:genetics* / Q000648:ultrastructure; D001483:Base Sequence; D015153:Blotting, Western; D006801:Humans; D007526:Isoelectric Point; D051379:Mice; D008969:Molecular Sequence Data; D009841:Oligonucleotides; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D011487:Protein Conformation; D051381:Rats
D001054:Apolipoproteins A; D009841:Oligonucleotides; C022205:apolipoprotein A-IV