The human low-density lipoprotein receptor mediates the transport of LDL into cells via endocytosis, and thus plays a major role in the clearance of lipoproteins from the blood. In 1973, by studying homozygous patient fibroblasts, Michael S. Brown and Joseph L.
Goldstein showed that the deficient protein in Familial Hypercholesterolemia was the LDL receptor (Goldstein and Brown, 1985).
The LDLR gene is localised at 19p13.1-p13.3, spans 45 kb and includes 18 exons (Lindgren et al. 1985; Yamamoto et al. 1984). It is ubiquitously expressed and encodes a glycoprotein of 839 amino acids that is pivotal in cholesterol homeostasis. The correspondence between the 6 functional domains of the protein and the exons of the LDLR gene is now well-established (Figure 1) (See Jeon and Blacklow 2005 for a review).
1. The signal peptide (21 amino acids) encoded by exon 1 is necessary for transport to the cell membrane and is cleaved during translocation into the endoplasmic reticulum (ER).
2. The ligand binding domain, encoded by exons 2 to 6 mediates the interaction with lipoproteins. This domain is made of seven modules named LDL receptor type A repeat (LR) and homologous to sequences of the protein C9 of the complement cascade (Sudolf et al. 1985). Each LR module is about 40 residues long, has six conserved cysteine residues, and contains a conserved acidic region near the C-terminus which serves as a calcium-binding site (Yamamoto et al. 1984, Fass et al. 1997). Mutational studies of the seven LR modules of the LDL receptor indicate that modules 3-7 all contribute significantly to the binding of LDL particles (Russel et al. 1989). Each of the LR5 and LR6 modules is essentially structurally independent of the other (North et al. 1999).
3. The EGF precursor homology domain (400 amino acids encoded by exons 7 to 14) is made of three 40 amino acids repeats homologous to the EGF precursor, and is involved in the dissociation of the receptor and the lipoprotein in the endocytosis machinery. The two first repeats are contiguous and separated from the third by a 280 amino acid sequence that contains five copies of a conserved motif (YWTD) repeated once for each of 40-60 amino acids. The first epidermal growth factor-like repeat (EGF-A) in the EGF homology domain interacts in a sequence-specific manner with proprotein convertase subtilisin/kexin type 9 (PCSK9) (Zhang et al. 2007, Kwon et al. 2008). PCSK9 post-translationally regulates hepatic LDL receptors by binding to them on the cell surface and by leading to their degradation. Gain-of-function mutations that increase the affinity of PCSK9 toward the receptor and increase plasma LDL-cholesterol levels in humans, have been reported in the PCSK9 gene associated with Autosomal Dominant Hypercholesterolemia (Abifadel et al. 2003, 2009). Loss-of-function mutations that decrease the affinity of PCSK9 toward the receptor have also been reported in the PCSK9 gene associated with low plasma levels of LDL (Cohen et al. 2005).
4. Exon 15 encodes a 58 amino acid sequence that is enriched in serines and threonines, which serve as attachment sites for O-linked sugar chains. The absence of this exon has no significant functional consequence in cultured hamster fibroblasts (Davis et al. 1986).
5. The 22 amino acids membrane-anchoring domain, encoded by exon 16 and the 5' end of exon 17, is essential to the attachment of the receptor to the cell membrane.
6. The 50 amino acid cytoplasmic tails, encoded by the remainder of exon 17 and the 5' end of exon 18, are involved in the endocytosis of the protein. The NPXY motif was shown to interact with the AP-2 clathrin adaptor and thus is important in the localisation of the receptor in coated pits on the cell surface. The NPXY motif was also shown to interact with the phosphotyrosine binding (PTB) domain of a specific clathrin adaptor protein encoded by the LDLRAP1 gene. Mutations in the LDLRAP1 gene have been reported in Autosomal Recessive Hypercholesterolemia (Garcia et al. 2001, Soutar 2010).
The reminder of exon 18 specifies the 2,6 kb 3' untranslated region of the mRNA.
In normal fibroblasts, the precursor protein is modified in the ER: the 21 amino acid signal peptide is cleaved and the precursor of 120 kDa is O-glycosylated to give rise to the 160 kDa protein. The resultant mature protein is transported from the Golgi apparatus to the cell surface within 30 minutes. The transmembrane receptor is present at the surface of most cell types and mediates the transport of LDL into cells, via receptor-mediated endocytosis, thus playing a pivotal role in cholesterol homeostasis (Goldstein and Brown, 2009). By endosome acidification, the lipoparticle is dissociated from the receptor, degraded and the receptor recycles back into the membrane.
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