Apolipoprotein Gene Structure and Function

Abstract

Plasma lipoproteins are lipid–protein complexes that circulate in blood. The protein components in these complexes are called apolipoproteins. The genes for the ‘soluble’ apolipoproteins, that is apoA1, A2, A4, A5, C1, C2, C3 and apoE, are structurally and evolutionarily related; they display similar structures that include four exons and three introns in specific locations (except A4, which contains only two introns, missing intron 1 in the 5′‐untranslated region). The proteins contain internal repeats of well‐defined amphipathic lipid‐binding motifs. ApoB‐100 is an ‘insoluble’ apolipoprotein in low‐density lipoprotein. ApoB mRNA editing in the small intestine generates a premature stop codon; translation of the edited mRNA produces apoB‐48, a protein ∼48% the size of apoB‐100 that is required for the biogenesis of chylomicrons. Apo(a) is a large glycoprotein which is covalently linked to apoB‐100 by a disulfide bond. Such apo B‐100‐apo(a) complex is a distinguishing feature of lipoprotein(a) (Lp(a)). In addition to the classic apolipoproteins, a host of other proteins have been found in lipoproteins. These proteins are often better known for their nonlipoprotein‐related functions, and their genes are structurally unrelated to those of the classic apolipoproteins. Many of the gene products discussed in this article play important roles in disease pathogenesis, diagnosis, prognostication and therapy.

Key Concepts

  • Apolipoproteins are the main protein components of lipoproteins.
  • Apolipoproteins display other specialised functions in addition to their role as lipid carriers.
  • A few apolipoproteins have been found to be predictors of neurodegenerative diseases or as potential prognostic markers of several types of cancers.
  • Some apolipoproteins are modulators of both innate and adaptive immune responses.
  • The ApoA1/C3/A4 gene cluster plays multiple pathophysiologic roles in lipoprotein metabolism and maintenance of plasma lipid levels and, as such, may influence the risk of cardiovascular disease development.
  • ApoB‐100, the major apolipoprotein in LDL and VLDL, and apoB‐48, an essential apolipoprotein in chylomicron biogenesis, have structural elements that are very different from those of the soluble apolipoproteins. Studies on the biogenesis of apoB‐48 led to the discovery of eukaryotic RNA editing.
  • Plasma levels of Lp(a) are a major independent risk indicator of premature coronary artery disease and stroke.

Keywords: Alzheimer disease; apolipoproteins; cardiovascular disease; lipocalins; lipoproteins; lipid transport; neurodegenerative disease

Figure 1. Structural organisation of genes encoding human apolipoprotein (Apo) A‐I, A‐II, A‐IV, A‐V, C‐I, C‐II, C‐III and E. The wide bars represent the exons and are divided into several regions: the open bars at the two ends represent the 5′ and 3′ untranslated regions; the hatched bars, the signal peptide and other processed regions; and the solid bars, the mature peptide regions of the respective genes. The numbers above the exons indicate exon length (in nucleotides). Structure and length are based on the GRCh37 assembly of the human genome.
Figure 2. Internal repeats of soluble human apolipoproteins. (a) The last 33 amino acids of exon 3 (exon 2 for apoA‐IV and apoA‐V) can be divided into three repeats of 11 amino acids. The various colours indicate amino acid characteristics as follows: purple: helix‐breaking proline (P); red: acidic residues aspartate (D) and glutamate (E); blue: basic residues arginine (R) and lysine (K) and green: hydrophobic residues methionine (M), valine (V), leucine (L), isoleucine (I), phenylalanine (F), tyrosine (Y) and tryptophan (W). The remaining amino acids – glycine (G), alanine (A), serine (S), threonine (T), asparagine (N), glutamine (Q), histidine, (H) and cysteine (C) – are not coloured and are considered to have indifferent characteristics. Any column containing four or more amino acids of a single colour is said to possess that characteristic, and the amino acids of that characteristic are boxed. Numbers along the left margin are residue numbers in the mature peptide. (b) Most of the repeats in exon 4 are 22‐mers, each of which is made up of two 11‐mers, and the other repeats are 11‐mers. If more than 18 amino acids in a column are of a single colour, the amino acids with that characteristic are boxed.
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Further Reading

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Martín‐Campos, Jesús M, Chang, Benny, Blanco‐Vaca, Francisco, Chan, Lawrence, and Julve, Josep(Apr 2017) Apolipoprotein Gene Structure and Function. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005909.pub3]