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

Christoffersen, Christina; Ahnström, Josefin LU ; Axler, Olof LU ; Christensen, Erik Ilso; Dahlbäck, Björn LU and Nielsen, Lars Bo (2008) In Journal of Biological Chemistry 283(27). p.18765-18772
Abstract
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
283
issue
27
pages
18765 - 18772
publisher
ASBMB
external identifiers
  • wos:000257165600033
  • scopus:49649084480
ISSN
1083-351X
DOI
10.1074/jbc.M800695200
language
English
LU publication?
yes
id
959e6d03-4243-441b-b1fd-30df88d632eb (old id 1186869)
date added to LUP
2008-09-04 09:27:36
date last changed
2017-08-13 03:37:12
@article{959e6d03-4243-441b-b1fd-30df88d632eb,
  abstract     = {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.},
  author       = {Christoffersen, Christina and Ahnström, Josefin and Axler, Olof and Christensen, Erik Ilso and Dahlbäck, Björn and Nielsen, Lars Bo},
  issn         = {1083-351X},
  language     = {eng},
  number       = {27},
  pages        = {18765--18772},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {The signal peptide anchors apolipoprotein m in plasma lipoproteins and prevents rapid clearance of apolipoprotein M from plasma},
  url          = {http://dx.doi.org/10.1074/jbc.M800695200},
  volume       = {283},
  year         = {2008},
}