The low-density lipoprotein receptor (LDLR) is the major cholesterol-carrying lipoprotein of plasma acting to regulate cholesterol homeostasis in mammalian cells. The LDL receptor binds LDL and transports it into cells by acidic endocytosis. In order to be internalized the receptor-ligand complex must first cluster into clathrin-coated pits. Once inside the cell the LDLR separates from its ligand which is degraded in the lysosomes while the receptor returns to the cell surface . The internal dissociation of the LDLR with its ligand is mediated by proton pumps within the walls of the endosome that lower the pH. The LDLR is a multi-domain protein containing:
- The ligand-binding domain contains seven or eight 40-amino acid LDLR class A (cysteine-rich) repeats each of which contains a coordinated calcium ion and six cysteine residues involved in disulphide bond formation . Similar domains have been found in other extracellular and membrane proteins .
- The second conserved region contains two EGF repeats followed by six LDLR class B (YWTD) repeats and another EGF repeat. The LDLR class B repeats each contain a conserved YWTD motif and is predicted to form a beta-propeller structure . This region is critical for ligand release and recycling of the receptor .
- The third domain is rich in serine and threonine residues and contains clustered O-linked carbohydrate chains.
- The fourth domain is the hydrophobic transmembrane region.
- The fifth domain is the cytoplasmic tail that directs the receptor to clathrin-coated pits.
LDLR is closely related in structure to several other receptors including LRP1 LRP1b megalin/LRP2 VLDL receptor lipoprotein receptor MEGF7/LRP4 and LRP8/apolipoprotein E receptor2); these proteins participate in a wide range of physiological processes including the regulation of lipid metabolism protection against atherosclerosis neurodevelopment and transport of nutrients and vitamins
.This entry represents the LDLR class A (cyateine-rich) repeat which contains 6 disulphide-bound cysteines and a highly conserved cluster of negatively charged amino acids of which many are clustered on one face of the module
. In LDL receptors the class A domains form the binding site for LDL and calcium. The acidic residues between the fourth and sixth cysteines are important for high-affinity binding of positively charged sequences in LDLR's ligands. The repeat consists of a beta-hairpin structure followed by a series of beta turns. In the absence of calcium LDL-A domains are unstructured; the bound calcium ion imparts structural integrity. Following these repeats is a 350 residue domain that resembles part of the epidermal growth factor (EGF) precursor. Numerous familial hypercholestorolemia mutations of the LDL receptor alter the calcium coordinating residue of LDL-A domains or other crucial scaffolding residues.