LDL receptor

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LDL receptor
LDL receptor
Surface model of the extracellular domain of the LDLR according to PDB  1N7D

Existing structural data : 1ajj , 1d2j , 1f5y , 1f8z , 1hj7 , 1hz8 , 1i0u , 1ijq , 1ldl , 1ldr , 1n7d , 1xfe , 2fcw

Properties of human protein
Mass / length primary structure 839 amino acids; 93.1 kDa
Identifier
Gene name LDLR
External IDs
Occurrence
Homology family LDL receptor
Parent taxon multicellular animals
Orthologue
human House mouse
Entrez 3949 16835
Ensemble ENSG00000130164 ENSMUSG00000032193
UniProt P01130 Q3TVR4
Refseq (mRNA) NM_000527 XM_979020
Refseq (protein) NP_000518 XP_984114
Gene locus Chr 19: 11.06 - 11.1 Mb Chr 9: 21.47 - 21.5 Mb
PubMed search 3949 16835

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

Joseph Leonard Goldstein and Michael S. Brown were awarded the Nobel Prize in 1985 for elucidating the uptake mechanism used by the LDL receptor and its importance for the cholesterol balance.

synthesis

LDL receptors are synthesized when the cholesterol concentration within the cell is too low. Transcription of the LDL receptor gene is activated by SREBP2 .

The 44.36 kilobases long gene encoding the receptor, contains 18 exons . The 5174 bases of the mRNA are translated at the endoplasmic reticulum into a protein containing 839 amino acids and weighing 93.1  kDa . This is glycosylated in the Golgi apparatus and then transported to the cell surface. About 700 of the 839 amino acids form the extracellular part of the receptor.

function

Transport of LDL from the blood plasma into the cell

LDL receptors are found on almost all cell types, as they ensure that the body's cells are supplied with the cholesterol transported in the LDL . The loaded receptors concentrate at certain points on the cell surface, so-called coated pits , and are channeled into the cell together with the LDL particles within a few minutes by endocytosis . Here, the coated pits constrict from the plasma membrane in the direction of the cell interior and form small, membrane-covered spheres, the coated vesicles . These vesicles are stabilized by a clathrin shell, which consists of many clathrin molecules (in the form of triskelions ) attached to one another . The clathrin sheath disintegrates shortly after the vesicle is constricted, which then becomes a so-called endosome . In this, the pH falls continuously while the endosome "matures". In a stage called CURL (Compartment for Uncoupling of Receptor and Ligand) , the LDL separates from the LDL receptor due to the acidic environment.

While the receptors are again transported to the surface of the cell membrane (receptor recycling), the LDL-containing endosomes fuse with lysosomes to form secondary lysosomes inside the cell . There the LDL particles are broken down enzymatically. The protein component is broken down into amino acids and the cholesterol esters are split into cholesterol and free fatty acids by a lysosomal lipase . The cholesterol released in this way can then be inserted into the cell membrane (see also membrane transport ), used in the corresponding tissues for the synthesis of steroid hormones or stored as cholesterol esters . Alternatively, LDL is taken up in cells via the scavenger pathway .

Ingestion of other proteins

The LDL receptor is also the protein that transports Tat protein of the HI virus into neurons . It is therefore a factor in HIV infection .

Gene defect of the receptor

A genetic defect in the LDL receptor is the cause of hereditary familial hypercholesterolemia . The patients have few or no functioning LDL receptors. In the homozygous form of familial hypercholesterolemia (HoFH), in particular , there is an extensive loss of function of the LDL receptor, while in the heterozygous form of the disease there is usually residual function of the receptor. Since both the transcription of the LDL receptor and the cellular self-synthesis of cholesterol are reversely regulated by intracellular cholesterol, a vicious circle arises with the result of a dramatically increased LDL cholesterol level in the serum, which is accompanied by an intracellular overproduction of cholesterol. Some of those affected suffer from rapidly spreading arteriosclerosis even in childhood . Patients with the homozygous form usually have total cholesterol values ​​of 650 to 1000 mg / dl and LDL cholesterol values ​​of> 500 mg / dl.

In HoFH patients, there is a direct connection between increased LDL cholesterol levels and the risk of cardiovascular events (such as heart attack, stroke). For the homozygous form of familial hypercholesterolemia (HoFH), pronounced arteriosclerosis is typical even at a young age.

The cholesterol-dependent transcription regulation of the LDL receptor can, however, be used for the therapy of heterozygous LDL receptor defects: By pharmacological inhibition of cellular cholesterol synthesis ( statins ), the cells are depleted of cholesterol and increase the transcription of the healthy allele so that the LDL receptor levels reach values ​​that are similar to those of healthy people. As a result, the uptake of LDL in the cell increases and the elevated LDL levels in the serum are reduced.

In patients with homozygous familial hypercholesterolemia (HoFH), this therapeutic approach usually works only inadequately: the genetic defect usually severely affects the binding of LDL cholesterol to the LDL receptors. A treatment approach approved in 2013 for HoFH patients is the inhibition of the microsomal transport protein (MTP) with the MTP inhibitor lomitapid .

Individual evidence

  1. ↑ a b UniProt P01130
  2. ↑ The Nobel Foundation : The Nobel Prize in Physiology or Medicine 1985 ( engl. ) Accessed 6 January 2010.
  3. ↑ D'Eustachio, P .: LDL endocytosis ( English ) reactome.org. Retrieved on January 6, 2010.  ( Page no longer available , search in web archives )  Info: The link was automatically marked as defective. Please check the link according to the instructions and then remove this notice.@1@ 2Template: dead link / reactome.org  
  4. ^ H. Jeon, SC Blacklow: Structure and physiologic function of the low-density lipoprotein receptor . In: Annu. Rev. Biochem. . 74, 2005, pp. 535-562. doi : 10.1146 / annurev.biochem.74.082803.133354 . PMID 15952897 .
  5. ↑ Y. Liu, M. Jones, CM Hingtgen et al. : Uptake of HIV-1 tat protein mediated by low-density lipoprotein receptor-related protein disrupts the neuronal metabolic balance of the receptor ligands . In: Nat. Med. . 6, No. 12, December 2000, pp. 1380-1387. doi : 10.1038 / 82199 . PMID 11100124 .
  6. ^ AD Marais: Familial hypercholesterolaemia . In: Clin. Biochem. Rev. Volume 25, No. 1, 2004, pp. 49-86.
  7. ^ A b F. J. Raal, RD Santos: Homozygous familial hypercholesterolemia: Current perspectives on diagnosis and treatment . In: Atherosclerosis. Volume 223, No. 2, 2012, pp. 262-268.
  8. ↑ JL Goldstein, HH Hobbs et al .: Familial hypercholesterolemia . New York, McGraw-Hill 2001
  9. ↑ S. Moorjani, M. Roy et al .: Mutations of low-density-lipoprotein-receptor gene, variation in plasma cholesterol, and expression of coronary heart disease in homozygous familial hypercholesterolaemia . In: Lancet , Volume 341, No. 8856, 1993, pp. 1303-1306.
  10. ↑ Rader DJ, Cohen J, Hobbs HH. Monogenic hypercholesterolemia: new insights in pathogenesis and treatment . J Clin Invest 2003; 111: 1795-1803
  11. ^ Z. Reiner et al .: ESC / EAS guidelines for the management of dyslipidaemias . In: European Heart Journal , Volume 32, 2011, pp. 1769-1818.
  12. ^ Y. Saito: Critical appraisal of the role of pitavastatin in treating dyslipidemias and achieving lipid goals . In: Vasc Health Risk Manag . 5, 2009, pp. 921-936. PMID 19997573 . PMC 2788597 (free full text).

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