Esser V, Russell D W
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas 75235.
J Biol Chem. 1988 Sep 15;263(26):13276-81.
Certain individuals with familial hypercholesterolemia (FH) produce mutant forms of the low density lipoprotein (LDL) receptor that fail to move from the endoplasmic reticulum to the Golgi complex. Here, we describe the cloning and expression of one such mutant allele, FH 429. The mutation causes a substitution of a Val for a Gly at residue 544. When recreated in an expressible cDNA, this substitution gives rise to an LDL receptor that is not transported to the cell surface and is rapidly degraded. Three previously mapped transport-deficient alleles of the LDL receptor were traced to the cysteine-rich repeats of the protein, suggesting that the generation of non-disulfide-bonded (free) cysteines might cause the block in transport. The FH 429 mutation is not located in a cysteine-rich region, however. We have attempted to test the role of cysteine by expressing mutant cDNAs that encode proteins blocked in transport and predicted to contain free cysteines. The results suggest that free cysteines are not obligatory for the blocked intracellular movement of mutant LDL receptors.
某些患有家族性高胆固醇血症（FH）的个体产生低密度脂蛋白（LDL）受体的突变形式，这些突变受体无法从内质网转运至高尔基体复合体。在此，我们描述了一种此类突变等位基因FH 429的克隆与表达。该突变导致第544位残基处的甘氨酸被缬氨酸取代。当在可表达的cDNA中重现此取代时，这种取代产生一种无法转运至细胞表面且会迅速降解的LDL受体。此前定位的三个LDL受体转运缺陷等位基因被追溯至该蛋白富含半胱氨酸的重复序列，这表明非二硫键结合（游离）半胱氨酸的产生可能导致转运受阻。然而，FH 429突变并不位于富含半胱氨酸的区域。我们试图通过表达编码在转运中受阻且预计含有游离半胱氨酸的蛋白质的突变cDNA来测试半胱氨酸的作用。结果表明，游离半胱氨酸对于突变LDL受体在细胞内的受阻移动并非必不可少。
