LDL receptor

The Low-Density Lipoprotein (LDL) Receptor is a mosaic protein of 839 amino acids (after removal of 21-amino acid signal peptide) that mediates the endocytosis of cholesterol-rich LDL. It is a cell-surface receptor that recognizes the apoprotein B100, which is embedded in the outer phospholipid layer of LDL particles. The receptor also recognizes the apoE protein found in chylomicron remnants and VLDL remnants (IDL). In humans, the LDL receptor protein is encoded by the LDLR gene. It belongs to the Low density lipoprotein receptor gene family.

Michael S. Brown and Joseph L. Goldstein were awarded the 1985 Nobel Prize in Physiology or Medicine for their identification of the Low Density Lipoprotein (LDL) Receptor and its relation to cholesterol metabolism and familial hypercholesterolemia.

Clinical significance

LDL is directly involved in the development of atherosclerosis, due to accumulation of LDL-cholesterol in the blood. Atherosclerosis is the process responsible for the majority of cardiovascular diseases.

Hyperthyroidism may be associated with hypocholesterolaemia via upregulation of the LDL receptor, and hypothyroidism with the converse

Function

LDL receptor complexes are present in clathrin-coated pits (or buds) on the cell surface, which when bound to LDL-cholesterol via adaptin, are pinched off to form clathrin-coated vesicles inside the cell. This allows LDL-cholesterol to be bound and internalized in a process known as endocytosis and prevents the LDL just diffusing around the membrane surface. This occurs in all nucleated cells, but mainly in the liver which removes ~70% of LDL from the circulation.

Once the coated vesicle is internalized it will shed its clathrin coat and will fuse with an acidic late endosome. The change in pH causes a conformational change in the receptor that releases the bound LDL particle. The receptors are then either destroyed or they can be recycled via the endocytic cycle back to the surface of the cell where the neutral pH will cause the receptor to revert to its native conformation ready to receive another LDL particle.

Synthesis of receptors in the cell is regulated by the level of free intracellular cholesterol; if it is in excess for the needs of the cell then the transcription of the receptor gene will be inhibited. LDL receptors are translated by ribosomes on the endoplasmic reticulum and are modified by the Golgi apparatus before travelling in vesicles to the cell surface.

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles.

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File:StatinPathway_WP430.png

Statin Pathway edit

Structure

Gene

The gene coding the LDL receptor is split into 18 exons. Exon 1 contains a signal sequence that localises the receptor to the endoplasmic reticulum for transport to the cell surface. Beyond this, exons 2-6 code the ligand binding region; 7-14 code the EGF domain; 15 codes the oligosaccharide rich region; 16 (and some of 17) code the membrane spanning region; and 18 (with the rest of 17) code the cytosolic domain. The LDL receptor can be described as a chimeric protein. It is made up of a number of functionally distinct domains that can function independently of each other.

Protein

The N-terminal domain of the LDL receptor, which is responsible for ligand binding, is composed of seven sequence repeats (~50% identical). Each repeat, referred to as a class A repeat or LDL-A, contains roughly 40 amino acids, including 6 cysteine residues that form disulfide bonds within the repeat. Additionally, each repeat has highly conserved acidic residues which it uses to coordinate a single calcium ion in an octahedral lattice. Both the disulfide bonds and calcium coordination are necessary for the structural integrity of the domain during the receptor's repeated trips to the highly acidic interior of the endosome. The exact mechanism of interaction between the class A repeats and ligand (LDL) is unknown, but it is thought that the repeats act as "grabbers" to hold the LDL. Binding of ApoB requires repeats 2-7 while binding ApoE requires only repeat 5 (thought to be the ancestral repeat).

Next to the ligand binding domain is an epidermal growth factor (EGF) precursor homology domain (EGFP domain). This shows approximately 30% homology with the EGF precursor gene. There are three "growth factor" repeats; A, B and C. A and B are closely linked while C is separated by the YWTD repeat region, which adopts a beta-propeller conformation (LDL-R class B domain). It is thought that this region is responsible for the pH-dependent conformational shift that causes bound LDL to be released in the endosome.

A third domain of the protein is rich in O-linked oligosaccharides but appears to show little function. Knockout experiments have confirmed that no significant loss of activity occurs without this domain. It has been speculated that the domain may have ancestrally acted as a spacer to push the receptor beyond the extracellular matrix.

The single transmembrane domain of 22 (mostly) non-polar residues crosses the plasma membrane in a single alpha helix.

The cytosolic C-terminal domain contains ~50 amino acids, including a signal sequence important for localizing the receptors to clathrin-coated pits and for triggering receptor-mediated endocytosis after binding. Portions of the cytosolic sequence have been found in other lipoprotein receptors, as well as in more distant receptor relatives.

Mutations

Mutations in the gene encoding the LDL receptor are known to cause familial hypercholesterolaemia.

There are 5 broad classes of mutation of the LDL receptor.

• Class 1 mutations affect the synthesis of the receptor in the endoplasmic reticulum (ER).
• Class 2 mutations prevent proper transport to the Golgi body needed for modifications to the receptor.
  • e.g. a truncation of the receptor protein at residue number 660 leads to domains 3,4 and 5 of the EGF precursor domain being missing. This precludes the movement of the receptor from the ER to the Golgi, and leads to degradation of the receptor protein.
• Class 3 mutations stop the binding of LDL to the receptor.
  • e.g. repeat 6 of the ligand binding domain (N-terminal, extracellular fluid) is deleted.
• Class 4 mutations inhibit the internalisation of the receptor-ligand complex.
  • e.g. "JD" mutant results from a single point mutation in the NPVY domain (C-terminal, cytosolic; Y residue converted to a C, residue number 807). This domain recruits clathrin and other proteins responsible for the endocytosis of LDL, therefore this mutation inhibits LDL internalization.
• Class 5 mutations give rise to receptors that cannot recycle properly. This leads to a relatively mild phenotype as receptors are still present on the cell surface (but all must be newly synthesised).

External links

• Description of LDL receptor pathway at the Brown - Goldstein Laboratory webpage
• LDL Receptor at the US National Library of Medicine Medical Subject Headings (MeSH)