The Low-Density Lipoprotein (LDL) Receptor (LDL-R) is a mosaic protein of 839 amino acids (after removal of the 21-amino acid signal peptide) that mediates cholesterol-rich LDL endocytosis. It is a cell surface receptor that recognizes apoprotein B100, which is embedded in the outer phospholipid layer of LDL particles. The receptor also recognizes the apoE protein found in the remnants of chylomicron and the remains of VLDL (IDL). In humans, LDL receptor proteins are encoded by the LDLR gene on chromosome 19. These include the family of low-density lipoprotein receptor genes. This is most significantly expressed in bronchial epithelial cells and the adrenal glands and cortical tissues.
Michael S. Brown and Joseph L. Goldstein were awarded the 1985 Nobel Prize in Physiology or Medicine for the identification of LDL-R and its association with the metabolism of cholesterol and familial hypercholesterolaemia. The LDLR gene also contains one of 27 SNPs associated with an increased risk of coronary artery disease.
Video LDL receptor
Struktur
Gene
The
This gene produces 6 isoforms through alternative splicing.
Protein
This protein belongs to the LDLR family and consists of a number of functionally different domains, including 3 domains like EGF, 7 LDL-R class A domains, and 6 repetitions of class B LDL-R.
The N-terminal domain of the LDL receptor, which is responsible for ligand binding, consists of seven repetition sequences (~ 50% identical). Each repetition, referred to as class A repeat or LDL-A , contains about 40 amino acids, including 6 cysteine ​​residues that form a disulphide bond in repetition. In addition, each repetition has a very sustainable acid residue which it uses to coordinate one calcium ion in the octahedral lattice. Both the disulfide bond and the calcium coordination are required for the structural integrity of the domain during the recurrent journey of this receptor to the interior of the highly acidic endosome. The exact mechanism of interaction between class A repeating and ligand (LDL) is unknown, but it is thought that repetition acts as a "hand" to hold LDL. Binding ApoB requires a repetition of 2-7 while binding ApoE requires only repetition 5 (considered an ancestral repetition).
In addition to the binding ligand domain is the homology domain of the predecessor of EGF (EGFP domain). This shows about 30% homology with EGF precursor genes. There are three repetitions of "growth factors"; A, B and C. A and B are closely related while C is separated by the repeating region of YWTD, which adopts the beta-number conformation (LDL-R domain class B ). It is estimated that this region is responsible for conformational shifts that depend on the pH that causes the LDL to be bound to be released in the endosome.
The third domain of the oligosaccharide-rich protein is O-linked but seems to indicate little function. Beat experiments have ensured that no significantly lost activity occurred without this domain. It has been speculated that the domains may have originally acted as spacers to induce receptors outside the extracellular matrix.
Single transmembrane domain of 22 (mostly) non-polar residues across the plasma membrane in a single alpha helix.
The C-terminal cytosol domain contains ~ 50 amino acids, including an important signal sequence to localize receptors to clathrin-coated holes and to trigger receptor-mediated endocytosis after binding. Part of the cytosolic sequence has been found in other lipoprotein receptors, as well as in distant relatives of receptors.
Mutations
Mutations in genes encoding LDL receptors are known to cause familial hypercholesterolaemia.
There are 5 broad classes of LDL receptor mutations:
- Class 1 mutations affect the synthesis of receptors in the endoplasmic reticulum (ER). Class 2 Class
- movements prevent the proper transport to the Golgi body required for modification to the receptor.
- for example. the receptor protein cutting on the residual number 660 leads to the 3.4 and 5 domains of the lost EGF precursor domain. This precludes the movement of receptors from ER to Golgi, and leads to the degradation of receptor proteins.
- Class 3 mutation stops the binding of LDL to the receptor.
- for example. repeat 6 ligand binding domains (N-terminal, extracellular fluid) removed.
- Class 4 mutations inhibit the internalization of ligand-receptor complexes.
- for example. "JD" mutant results from a single point mutation in the NPVY domain (C-terminal, cytosolic; Y residue is converted to C, the residual number 807). This domain recruits clathrin and other proteins responsible for LDL endocytosis, therefore this mutation inhibits the internalization of LDL.
Class 5 - Movements lead to receptors that can not recycle correctly. This causes a relatively mild phenotype because receptors still exist on the cell surface (but all must be newly synthesized).
Maps LDL receptor
Function
LDL receptors mediate cholesterol-rich LDL endocytosis and thus maintain LDL plasma levels. It occurs in all nucleated cells, but especially in the liver which removes ~ 70% of LDL from the circulation. The LDL receptors are clustered in clathrin-coated holes, and the coated holes are squeezed from the surface to form the coated endocytic vesicles that carry LDL into the cell. After internalization, the receptors dissociate from their ligand when they are exposed to low pH in the endosomes. After dissociation, the receptor folds back on itself to obtain a closed conformation and recycle it to the cell surface. Fast recycling of LDL receptors provides an efficient mechanism for sending cholesterol to cells. It has also been reported that in association with lipoprotein in the blood, viruses such as hepatitis C virus, Flaviviridae virus and bovine virus virus infections can enter the cell indirectly via endocytosis mediated by LDLR. In addition, LDLR modulation is associated with lymphatic dysfunction associated with early atherosclerosis. The synthesis of receptors in cells is governed by free intracellular cholesterol levels; if it is excessive for cell needs then receptor gene transcription will be inhibited. The LDL receptor is translated by the ribosome in the endoplasmic reticulum and modified by the Golgi apparatus before traveling in the vesicles to the cell surface.
Clinical interests
In humans, LDL is directly involved in the development of atherosclerosis, which is the process responsible for most cardiovascular diseases, due to the accumulation of LDL-cholesterol in the blood. Hyperthyroidism may be associated with hypocholesterolemia by increasing regulation of LDL receptors, and hypothyroidism with the opposite. A large number of studies have described the relevance of LDL receptors in the pathophysiology of atherosclerosis, metabolomic syndrome, and steatohepatitis. Previously, rare mutations in the LDL gene have been shown to contribute to the risk of myocardial infarction in individual families, whereas a common variant of more than 45 loci has been associated with a risk of myocardial infarction in the population. When compared with non-carriers, carriers of LDLR mutations have higher plasma LDL cholesterol, whereas APOA5 mutation carriers have higher plasma triglycerides. Recent evidence has linked MI risk with coding-sequence mutations in two genes functionally associated with APOA5, lipoprotein lipase and apolipoprotein C-III. Combined, these observations suggest that, as with LDL cholesterol, the irregular metabolism of triglyceride-rich lipoproteins contributes to MI risk. Overall, LDLR has high clinical relevance in blood lipids.
Tanda klinis
A multi-locus genetic risk score study based on a combination of 27 loci, including the LDLR gene, identifies individuals on an increased risk for both the incidence and incidence of recurrent coronary artery disease, as well as enhanced clinical benefit from statin therapy. The study was based on a community cohort study (Malmo Diet and Cancer Study) and four randomized controlled trials of primary prevention groups (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).
Interactive path map
Click on the genes, proteins and metabolites below to link to each article.
References
Further reading
External links
- Description of the LDL receptor path on the Brown - Goldstein Laboratory web page
- LDL Receptor at the National Library of Medicine US Subject of Medical Subject (MeSH)
Source of the article : Wikipedia
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