Intracellular and extracellular processing of human apolipoprotein A-I: secreted apolipoprotein A-I isoprotein 2 is a propeptide.
We have recently proposed that the major secreted isoprotein form of human apolipoprotein A-I (designated apo A-I2) is modified extracellularly to become the predominant apo A-I form seen in plasma (designated apo A-I4). In the current report we demonstrate that the primary translation product of human apo A-I (designated apo A-I2p) has a 24-amino-acid NH2-terminal extension with a sequence of Met-Lys-Ala-Ala-Val-Leu-Thr-Leu-Ala-Val-Leu-Phe- Leu-Thr-Gly-Ser-Gln-Ala-Arg-His-Phe-Trp-Gln-Gln. The first 18 amino acids of this NH2-terminal extension are cleaved intracellularly by the signal peptidase, resulting in the formation of apo A-I2, which is the secreted form of apo A-I. Sequence analysis of apo A-I2 confirmed that it contains a hexapeptide extension at its NH2 terminus compared to apo A-I4. This observation demonstrates that apo A-I2 is a propeptide and that the apo A-I2 to apo A-I4 conversion involves the removal of the NH2-terminal hexapeptide of apo A-I2 by a protease in plasma, lymph, or both. Our findings indicate that apo A-I is synthesized as a prepropeptide, which undergoes intracellular and extracellular proteolysis to attain the major plasma apo A-I4 isoprotein form.
D000595:Amino Acid Sequence; D000818:Animals; D016632:Apolipoprotein A-I; D001053:Apolipoproteins / Q000235:genetics / Q000378:metabolism*; D001054:Apolipoproteins A; D001483:Base Sequence; D002474:Cell-Free System; D004247:DNA / Q000032:analysis; D006801:Humans; D014176:Protein Biosynthesis; D011499:Protein Processing, Post-Translational; D051381:Rats
D016632:Apolipoprotein A-I; D001053:Apolipoproteins; D001054:Apolipoproteins A; D004247:DNA