LDL receptor

  • OMIM: 606945
  • UniProt: P01130
  • MGI: 96765

The LDL receptor (low density lipoprotein receptor ) is a protein that is anchored in cell membranes of all animals. It is a so-called membrane receptor that mediates specific binding to the apo B-100, the protein component of LDL with its dietary fats located outside of the cell binding sites. After LDL is bound, it is transported into the interior of the cell.

For the elucidation of the used by the LDL receptor uptake mechanism and the importance for the cholesterol metabolism Joseph Leonard Goldstein and Michael S. Brown were awarded the 1985 Nobel Prize.

Synthesis

The 44.36 kilobase gene coding for the receptor, contains 18 exons. The 5174 bases of the mRNA containing a 839 amino acids in the endoplasmic reticulum and translated 93.1 kDa protein. It is glycosylated in the Golgi apparatus and is then transported to the cell surface. Approximately 700 of the 839 amino acids form the extracellular portion of the receptor.

Function

Transport of LDL from the blood plasma into the cell

LDL receptors are found on virtually all cell types, as they ensure the supply to the body cells with the transported in LDL cholesterol. The loaded receptors are concentrated at particular points on the cell surface, so-called coated pits, and are funneled together with the LDL particles within a few minutes by endocytosis into the cell. Here, the lace coated pits on the plasma membrane toward the cell interior, forming small, membrane-enclosed spheres coated vesicles. These vesicles are stabilized by a Clathrinhülle consisting of many annealed clathrin molecules ( in the form of triskelions ). The Clathrinhülle disintegrates shortly after the constriction of the vesicle, which becomes a so-called endosome. In this continuously falls, the pH, during the endosome " matures ". In a CURL ( Compartment for Uncoupling of Receptor and Ligand ) above stage separates due to the acidic environment of the LDL LDL receptor.

While the receptors are transported to the surface of the cell membrane again ( receptor recycling) to merge within the cell, the LDL -containing endosomes with lysosomes to form secondary lysosomes. There, the LDL particles are degraded enzymatically. The protein portion is broken down into amino acids and the cholesterol ester cleaved by a lysosomal lipase in cholesterol and free fatty acids. The thus liberated cholesterol can then be inserted into the cell membrane (see membrane transport ) are stored as cholesterol esters used in the relevant tissues for the synthesis of steroid hormones or.

Absorption of other proteins

LDL - receptor is also that protein accomplished transporting Tat protein of HIV in neurons. It is therefore a factor in HIV infection.

Genetic defect of the receptor

A genetic defect in the LDL receptor is the cause of the inherited familial hypercholesterolemia. Patients have little or no functional LDL receptors. In particular in the homozygous form of familial hypercholesterolemia ( HoFH ) shows a loss of function of the utmost of the LDL receptor, whereas the heterozygous form of the disease usually still is present a residual function of the receptor. Since both the transcription of the LDL receptor and the cellular endogenous synthesis of cholesterol are regulated by intracellular cholesterol reverse, creating a vicious circle, with the consequence of a dramatic increase in LDL - cholesterol levels in the serum, which is accompanied by an intracellular overproduction of cholesterol. Even as a child suffer some patients are at a rapidly spreading atherosclerosis. Patients with the homozygous form mostly falling on that occasion with total cholesterol values ​​650-1000 mg / dl and LDL - cholesterol levels> 500 mg / dl.

In HoFH patients shows a direct correlation between elevated LDL cholesterol levels and the risk of cardiovascular events (such as heart attack, stroke). For the homozygous form of familial hypercholesterolemia ( HoFH ) is a distinct atherosclerosis at a young age typically.

The cholesterol- dependent transcriptional regulation of the LDL receptor may, however, be used for the treatment of heterozygous LDL - receptor defects: Pharmacological inhibition of cellular cholesterol synthesis inhibitors (statins ), the cells depleted of cholesterol and increase, so that the LDL receptor levels to achieve the transcription of the healthy allele values are similar to those of healthy subjects. As a result of LDL uptake into the cell and increase the elevated LDL level in serum can be reduced.

In patients with homozygous familial hypercholesterolemia ( HoFH ) this therapeutic approach usually works poorly: The genetic defect, the binding of LDL cholesterol is usually severely impaired to the LDL receptors. A 2013 approved treatment approach HoFH patients is the inhibition of microsomal transfer protein (MTP ) with the MTP inhibitor Lomitapid.

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