6-Aminohexanoic acid as a chemical chaperone for apolipoprotein(a).
Apolipoprotein (a) (apo(a)) is a component of the atherogenic lipoprotein, Lp(a). The efficiency with which apo(a) escapes the endoplasmic reticulum (ER) and is secreted by the liver is a major determinant of plasma Lp(a) levels. Apo(a) contains a series of domains homologous to plasminogen kringle (K) 4, each of which possesses a potential lysine-binding site. By using primary mouse hepatocytes expressing a 17K4 human apo(a) protein, we found that high concentrations (25-200 mM) of the lysine analog, 6-aminohexanoic acid (6AHA), increased apo(a) secretion 8-14-fold. This was accompanied by a decrease in apo(a) presecretory degradation. 6AHA inhibited accumulation of apo(a) in the ER induced by the proteasome inhibitor, lactacystin. Thus, 6AHA appeared to inhibit degradation by increasing apo(a) export from the ER. Significantly, 6AHA overcame the block in apo(a) secretion induced by the ER glucosidase inhibitor, castanospermine. 6AHA may therefore circumvent the requirement for calnexin and calreticulin interaction in apo(a) secretion. Sucrose gradients and a gel-based folding assay were unable to detect any influence of 6AHA on apo(a) folding. However, non-covalent or small, disulfide-dependent changes in apo(a) conformation would not be detected in these assays. Proline also increased the efficiency of apo(a) secretion. We propose that 6AHA and proline can act as chemical chaperones for apo(a).
Wang
J
J
Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, Texas 75235-9052, USA.
White
A L
AL
D015119:Aminocaproic Acid / Q000378:metabolism*; D000818:Animals; D001053:Apolipoproteins / Q000378:metabolism*; D053241:Apoprotein(a); D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D007212:Indolizines / Q000494:pharmacology; D017270:Lipoprotein(a); D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000378:metabolism*; D011392:Proline / Q000378:metabolism; D017510:Protein Folding; D054836:Indolizidines
D015119:Aminocaproic Acid; D001053:Apolipoproteins; D053241:Apoprotein(a); D007212:Indolizines; D017270:Lipoprotein(a); D018832:Molecular Chaperones; D011392:Proline; C037806:castanospermine; D054836:Indolizidines