Biology:LDL receptor

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Short description: Mammalian protein found in Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


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 LDLR 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 279 mg/dL, compared with 135 mg/dL 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.[4] 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.[10]

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

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 internalization of the receptor-ligand complex.
    • e.g. "JD" mutant results from a single point mutation in the NPVY domain (C-terminal, cytosolic; C residue converted to a Y, 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).[14]

Function

LDL receptor mediates the endocytosis of cholesterol-rich LDL and thus maintains the plasma level of LDL.[15] 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.[16] 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.[17] The rapid recycling of LDL receptors provides an efficient mechanism for delivery of cholesterol to cells.[18][19] 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.[20] LDLR has been identified as the primary mode of entry for the Vesicular stomatitis virus in mice and humans.[21] In addition, LDLR modulation is associated with early atherosclerosis-related lymphatic dysfunction.[22] 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.[23] 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 [citation needed]. Hyperthyroidism may be associated with hypocholesterolemia 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.[24][25] 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.[26] Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase and apolipoprotein C-III.[27][28] 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.[29][30]

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).[31]

Interactive pathway map

References

  1. ↑ "The LDL receptor gene: a mosaic of exons shared with different proteins". Science 228 (4701): 815–22. May 1985. doi:10.1126/science.2988123. PMID 2988123. Bibcode: 1985Sci...228..815S. 
  2. ↑ "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. doi:10.1073/pnas.81.9.2826. PMID 6326146. Bibcode: 1984PNAS...81.2826F. 
  3. ↑ "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. doi:10.1073/pnas.82.24.8567. PMID 3866240. Bibcode: 1985PNAS...82.8567L. 
  4. ↑ 4.0 4.1 "LDLR low density lipoprotein receptor [Homo sapiens (human) - Gene - NCBI"]. https://www.ncbi.nlm.nih.gov/gene/3949. 
  5. ↑ "The low-density lipoprotein receptor gene family: a cellular Swiss army knife?". Trends in Cell Biology 12 (6): 273–80. June 2002. doi:10.1016/S0962-8924(02)02282-1. PMID 12074887. 
  6. ↑ "BioGPS - your Gene Portal System". http://biogps.org/#goto=genereport&id=3949. 
  7. ↑ "The Nobel Prize in Physiology or Medicine 1985" (Press release). The Royal Swedish Academy of Science. 1985. Retrieved 2010-07-01.
  8. ↑ "How LDL receptors influence cholesterol and atherosclerosis". Scientific American 251 (5): 58–66. November 1984. doi:10.1038/scientificamerican0984-52. PMID 6390676. Bibcode: 1984SciAm.251c..52K. 
  9. ↑ "Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction". Nature 518 (7537): 102–6. February 2015. doi:10.1038/nature13917. PMID 25487149. Bibcode: 2015Natur.518..102.. 
  10. ↑ 10.0 10.1 "LDLR - Low-density lipoprotein receptor precursor - Homo sapiens (Human) - LDLR gene & protein". https://www.uniprot.org/uniprot/P01130. 
  11. ↑ "The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA". Cell 39 (1): 27–38. November 1984. doi:10.1016/0092-8674(84)90188-0. PMID 6091915. 
  12. ↑ "LDL-receptor structure. Calcium cages, acid baths and recycling receptors". Nature 388 (6643): 629–30. August 1997. doi:10.1038/41672. PMID 9262394. Bibcode: 1997Natur.388..629B. 
  13. ↑ "Low-density lipoprotein receptor structure and folding". Cellular and Molecular Life Sciences 61 (19–20): 2461–70. October 2004. doi:10.1007/s00018-004-4090-3. PMID 15526154. 
  14. ↑ "Low Density Lipoprotein Receptor". LOVD v.1.1.0 - Leiden Open Variation Database. http://www.ucl.ac.uk/ldlr/Current/index.php?select_db=LDLR. 
  15. ↑ "Sorting an LDL receptor with bound PCSK9 to intracellular degradation". Atherosclerosis 237 (1): 76–81. November 2014. doi:10.1016/j.atherosclerosis.2014.08.038. PMID 25222343. 
  16. ↑ "The LDL receptor". Arteriosclerosis, Thrombosis, and Vascular Biology 29 (4): 431–8. April 2009. doi:10.1161/ATVBAHA.108.179564. PMID 19299327. 
  17. ↑ "Structure of the LDL receptor extracellular domain at endosomal pH". Science 298 (5602): 2353–8. December 2002. doi:10.1126/science.1078124. PMID 12459547. Bibcode: 2002Sci...298.2353R. https://digital.library.unt.edu/ark:/67531/metadc883196/. 
  18. ↑ "Monensin interrupts the recycling of low density lipoprotein receptors in human fibroblasts". Cell 24 (2): 493–502. May 1981. doi:10.1016/0092-8674(81)90340-8. PMID 6263497. 
  19. ↑ "Recycling receptors: the round-trip itinerary of migrant membrane proteins". Cell 32 (3): 663–7. March 1983. doi:10.1016/0092-8674(83)90052-1. PMID 6299572. 
  20. ↑ "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. doi:10.1073/pnas.96.22.12766. PMID 10535997. Bibcode: 1999PNAS...9612766A. 
  21. ↑ "LDL receptor and its family members serve as the cellular receptors for vesicular stomatitis virus". Proceedings of the National Academy of Sciences of the United States of America 110 (18): 7306–11. April 2013. doi:10.1073/pnas.1214441110. PMID 23589850. Bibcode: 2013PNAS..110.7306F. 
  22. ↑ "Effects of LDL Receptor Modulation on Lymphatic Function". Scientific Reports 6: 27862. 2016-01-01. doi:10.1038/srep27862. PMID 27279328. Bibcode: 2016NatSR...627862M. 
  23. ↑ "Identification of nucleotides responsible for enhancer activity of sterol regulatory element in low density lipoprotein receptor gene". The Journal of Biological Chemistry 265 (4): 2306–10. Feb 1990. doi:10.1016/S0021-9258(19)39976-4. PMID 2298751. 
  24. ↑ "TTC39B deficiency stabilizes LXR reducing both atherosclerosis and steatohepatitis". Nature 535 (7611): 303–7. July 2016. doi:10.1038/nature18628. PMID 27383786. Bibcode: 2016Natur.535..303H. 
  25. ↑ "The UK10K project identifies rare variants in health and disease". Nature 526 (7571): 82–90. October 2015. doi:10.1038/nature14962. PMID 26367797. Bibcode: 2015Natur.526...82T. 
  26. ↑ "Estrogen receptor-positive mammary tumorigenesis in TGFalpha transgenic mice progresses with progesterone receptor loss". Oncogene 26 (36): 5238–46. August 2007. doi:10.1038/sj.onc.1210340. PMID 17334393. 
  27. ↑ "Loss-of-function mutations in APOC3, triglycerides, and coronary disease". The New England Journal of Medicine 371 (1): 22–31. July 2014. doi:10.1056/NEJMoa1307095. PMID 24941081. 
  28. ↑ "Loss-of-function mutations in APOC3 and risk of ischemic vascular disease". The New England Journal of Medicine 371 (1): 32–41. July 2014. doi:10.1056/NEJMoa1308027. PMID 24941082. https://semanticscholar.org/paper/55f5e169d6f4d9a568cca4bbafe0790022e8bc16. 
  29. ↑ "Genomics: Variations in blood lipids". Nature 466 (7307): 703–4. August 2010. doi:10.1038/466703a. PMID 20686562. Bibcode: 2010Natur.466..703S. 
  30. ↑ "Biological, clinical and population relevance of 95 loci for blood lipids". Nature 466 (7307): 707–13. August 2010. doi:10.1038/nature09270. PMID 20686565. Bibcode: 2010Natur.466..707T. 
  31. ↑ "Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials". Lancet 385 (9984): 2264–71. June 2015. doi:10.1016/S0140-6736(14)61730-X. PMID 25748612. 

Further reading

External links




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