LDL receptor explained

The low-density lipoprotein receptor (LDL-R) is a mosaic protein of 839 amino acids (after removal of 21-amino acid signal peptide)[1] that mediates the endocytosis of cholesterol-rich low-density lipoprotein (LDL). It is a cell-surface receptor that recognizes apolipoprotein B100 (ApoB100), which is embedded in the outer phospholipid layer of very low-density lipoprotein (VLDL), their remnants - i.e. intermediate-density lipoprotein (IDL), and LDL particles. The receptor also recognizes apolipoprotein E (ApoE) which is found in chylomicron remnants and IDL. In humans, the LDL receptor protein is encoded by the gene on chromosome 19.[2] [3] [4] It belongs to the low density lipoprotein receptor gene family.[5] It is most significantly expressed in bronchial epithelial cells and adrenal gland and cortex tissue.[6]

Michael S. Brown and Joseph L. Goldstein were awarded the 1985 Nobel Prize in Physiology or Medicine for their identification of LDL-R[7] and its relation to cholesterol metabolism and familial hypercholesterolemia.[8] Disruption of LDL-R can lead to higher LDL-cholesterol as well as increasing the risk of related diseases. Individuals with disruptive mutations (defined as nonsense, splice site, or indel frameshift) in LDLR have an average LDL-cholesterol of, compared with for individuals with neither disruptive nor deleterious mutations. Disruptive mutations were 13 times more common in individuals with early-onset myocardial infarction or coronary artery disease than in individuals without either disease.[9]

Structure

Gene

The LDLR gene resides on chromosome 19 at the band 19p13.2 and 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 epidermal growth factor (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.

This gene produces 6 isoforms through alternative splicing.[10]

Protein

This protein belongs to the LDLR family and is made up of a number of functionally distinct domains, including 3 EGF-like domains, 7 LDL-R class A domains, and 6 LDL-R class B repeats.

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 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.[11] [12] [13]

Mutations

Loss-of-function 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:

Gain-of-function mutations decrease LDL levels and are a target of research to develop a gene therapy to treat refractory hypercholesterolemia.[15]

Function

LDL receptor mediates the endocytosis of cholesterol-rich LDL and thus maintains the plasma level of LDL.[16] This occurs in all nucleated cells, but mainly in the liver which removes ~70% of LDL from the circulation. LDL receptors are clustered in clathrin-coated pits, and coated pits pinch off from the surface to form coated endocytic vesicles that carry LDL into the cell.[17] After internalization, the receptors dissociate from their ligands when they are exposed to lower pH in endosomes. After dissociation, the receptor folds back on itself to obtain a closed conformation and recycles to the cell surface.[18] The rapid recycling of LDL receptors provides an efficient mechanism for delivery of cholesterol to cells.[19] [20] It was also reported that by association with lipoprotein in the blood, viruses such as hepatitis C virus, Flaviviridae viruses and bovine viral diarrheal virus could enter cells indirectly via LDLR-mediated endocytosis.[21] LDLR has been identified as the primary mode of entry for the Vesicular stomatitis virus in mice and humans.[22] In addition, LDLR modulation is associated with early atherosclerosis-related lymphatic dysfunction.[23] 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.[24] 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.

Clinical significance

In humans, LDL is directly involved in the development of atherosclerosis, which is the process responsible for the majority of cardiovascular diseases, due to accumulation of LDL-cholesterol in the blood . Hyperthyroidism may be associated with reduced cholesterol via upregulation of the LDL receptor, and hypothyroidism with the converse. A vast number of studies have described the relevance of LDL receptors in the pathophysiology of atherosclerosis, metabolic syndrome, and steatohepatitis.[25] [26] Previously, rare mutations in LDL-genes have been shown to contribute to myocardial infarction risk in individual families, whereas common variants at more than 45 loci have been associated with myocardial infarction risk in the population. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides.[27] Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase and apolipoprotein C-III.[28] [29] Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk. Overall, LDLR has a high clinical relevance in blood lipids.[30] [31]

Clinical marker

A multi-locus genetic risk score study based on a combination of 27 loci, including the LDLR gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmö Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).[32]

Further reading

External links

Notes and References

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  2. Francke U, Brown MS, Goldstein JL . Assignment of the human gene for the low density lipoprotein receptor to chromosome 19: synteny of a receptor, a ligand, and a genetic disease . Proceedings of the National Academy of Sciences of the United States of America . 81 . 9 . 2826–30 . May 1984 . 6326146 . 345163 . 10.1073/pnas.81.9.2826 . 1984PNAS...81.2826F . free .
  3. Lindgren V, Luskey KL, Russell DW, Francke U . Human genes involved in cholesterol metabolism: chromosomal mapping of the loci for the low density lipoprotein receptor and 3-hydroxy-3-methylglutaryl-coenzyme A reductase with cDNA probes . Proceedings of the National Academy of Sciences of the United States of America . 82 . 24 . 8567–71 . December 1985 . 3866240 . 390958 . 10.1073/pnas.82.24.8567 . 1985PNAS...82.8567L . free .
  4. Web site: LDLR low density lipoprotein receptor [Homo sapiens (human)] - Gene - NCBI]. www.ncbi.nlm.nih.gov. 2016-10-10.
  5. Nykjaer A, Willnow TE . The low-density lipoprotein receptor gene family: a cellular Swiss army knife? . Trends in Cell Biology . 12 . 6 . 273–80 . June 2002 . 12074887 . 10.1016/S0962-8924(02)02282-1 .
  6. Web site: BioGPS - your Gene Portal System. biogps.org. 2016-10-10.
  7. The Nobel Prize in Physiology or Medicine 1985 . The Royal Swedish Academy of Science . 1985 . 2010-07-01.
  8. Brown MS, Goldstein JL . How LDL receptors influence cholesterol and atherosclerosis . Scientific American . 251 . 5 . 58–66 . November 1984 . 6390676 . 10.1038/scientificamerican0984-52 . 1984SciAm.251c..52K .
  9. Do R, Stitziel NO, Won HH, Jørgensen AB, Duga S, Angelica Merlini P, etal . Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction . Nature . 518 . 7537 . 102–6 . February 2015 . 25487149 . 4319990 . 10.1038/nature13917 . 2015Natur.518..102. .
  10. Web site: LDLR - Low-density lipoprotein receptor precursor - Homo sapiens (Human) - LDLR gene & protein. www.uniprot.org. 2016-10-10.
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  19. Basu SK, Goldstein JL, Anderson RG, Brown MS . Monensin interrupts the recycling of low density lipoprotein receptors in human fibroblasts . Cell . 24 . 2 . 493–502 . May 1981 . 6263497 . 10.1016/0092-8674(81)90340-8. 29553611 .
  20. Brown MS, Anderson RG, Goldstein JL . Recycling receptors: the round-trip itinerary of migrant membrane proteins . Cell . 32 . 3 . 663–7 . March 1983 . 6299572 . 10.1016/0092-8674(83)90052-1. 34919831 .
  21. Agnello V, Abel G, Elfahal M, Knight GB, Zhang QX . Hepatitis C virus and other flaviviridae viruses enter cells via low density lipoprotein receptor . Proceedings of the National Academy of Sciences of the United States of America . 96 . 22 . 12766–71 . October 1999 . 10535997 . 23090 . 10.1073/pnas.96.22.12766. 1999PNAS...9612766A . free .
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