The signal peptide anchors apolipoprotein m in plasma lipoproteins and prevents rapid clearance of apolipoprotein M from plasma

Christina Christoffersen, Josefin Ahnström, Olof Axler, Erik Ilso Christensen, Björn Dahlbäck, Lars Bo Nielsen

Research output: Contribution to journalArticlepeer-review


Lipoproteins consist of lipids solubilized by apolipoproteins. The lipid-binding structural motifs of apolipoproteins include amphipathic alpha-helixes and beta-sheets. Plasma apolipoprotein (apo) M lacks an external amphipathic motif but, nevertheless, is exclusively associated with lipoproteins ( mainly high density lipoprotein). Uniquely, however, apoM is secreted to plasma without cleavage of its hydrophobic NH2-terminal signal peptide. To test whether the signal peptide serves as a lipoprotein anchor for apoM in plasma, we generated mice expressing a mutated apoM(Q22A) cDNA in the liver ( apoM(Q22A)-Tg mice (transgenic mice)) and compared them with mice expressing wild-type human apoM( apoM-Tg mice). The substitution of the amino acid glutamine 22 with alanine in apoMQ22A results in secretion of human apoM without a signal peptide. The human apoM mRNA level in liver and the amount of human apoM protein secretion from hepatocytes were similar in apoM-Tg and apoMQ22A-Tg mice. Nevertheless, human apoM was not detectable in plasma of apoMQ22A-Tg mice, whereas it was easily measured in the apoM-Tg mice. To examine the plasma metabolism, recombinant apoM lacking the signal peptide was produced in Escherichia coli and injected into wild-type mice. The apoM without signal peptide did not associate with lipoproteins and was rapidly cleared in the kidney. Accordingly, ligation of the kidney arteries in apoMQ22A-Tg mice resulted in rapid accumulation of human apoM in plasma. The data suggest that hydrophobic signal peptide sequences, if preserved upon secretion, can anchor plasma proteins in lipoproteins. In the case of apoM, this mechanism prevents rapid loss by filtration in the kidney.
Original languageEnglish
Pages (from-to)18765-18772
JournalJournal of Biological Chemistry
Issue number27
Publication statusPublished - 2008

Subject classification (UKÄ)

  • Medicinal Chemistry


Dive into the research topics of 'The signal peptide anchors apolipoprotein m in plasma lipoproteins and prevents rapid clearance of apolipoprotein M from plasma'. Together they form a unique fingerprint.

Cite this