SSF57424

LDL receptor-like module

SUPERFAMILY entry
Member databaseSUPERFAMILY
SUPERFAMILY typehomologous superfamily

Description
Imported from IPR036055

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
[4]
. 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
[1]
. Similar domains have been found in other extracellular and membrane proteins
[5]
.


 * 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 β-propeller structure
[2]
. This region is critical for ligand release and recycling of the receptor
[3]
.


 * 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
[6]
.

This entry represents the LDLR class A (cysteine-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
[5]
. 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 β-hairpin structure followed by a series of β 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 hypercholesterolemia mutations of the LDL receptor alter the calcium coordinating residue of LDL-A domains or other crucial scaffolding residues.

References
Imported from IPR036055

1.The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA. Yamamoto T, Davis CG, Brown MS, Schneider WJ, Casey ML, Goldstein JL, Russell DW. Cell 39, 27-38, (1984). View articlePMID: 6091915

2.An extracellular beta-propeller module predicted in lipoprotein and scavenger receptors, tyrosine kinases, epidermal growth factor precursor, and extracellular matrix components. Springer TA. J. Mol. Biol. 283, 837-62, (1998). View articlePMID: 9790844

3.Acid-dependent ligand dissociation and recycling of LDL receptor mediated by growth factor homology region. Davis CG, Goldstein JL, Sudhof TC, Anderson RG, Russell DW, Brown MS. Nature 326, 760-5, (1987). View articlePMID: 3494949

4.A receptor-mediated pathway for cholesterol homeostasis. Brown MS, Goldstein JL. Science 232, 34-47, (1986). View articlePMID: 3513311

5.Three-dimensional structure of a cysteine-rich repeat from the low-density lipoprotein receptor. Daly NL, Scanlon MJ, Djordjevic JT, Kroon PA, Smith R. Proc. Natl. Acad. Sci. U.S.A. 92, 6334-8, (1995). View articlePMID: 7603991

6.The LDL receptor-related protein (LRP) family: an old family of proteins with new physiological functions. May P, Woldt E, Matz RL, Boucher P. Ann. Med. 39, 219-28, (2007). View articlePMID: 17457719

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