LDL receptor
The Low-Density Lipoprotein (LDL) Receptor is a mosaic protein of ~840 amino acids (after removal of signal peptide) that mediates the endocytosis of cholesterol-rich LDL. It is a cell-surface receptor that recognizes the apoprotein B100 which is embedded in the phospholipid outer layer of LDL particles. The receptor also recognizes the apoE protein found in chylomicron remnants and VLDL remnants (IDL). In humans, the LDL receptor protein[1] is encoded by the LDLR gene.[2][3] It belongs to the Low density lipoprotein receptor gene family.[4]
Brown and Goldstein won a Nobel Prize for their identification of the Low Density Lipoprotein (LDL) receptor in 1985[5] while they were studying familial hypercholesterolemia.[6]
Clinical significance
LDL is directly involved in the development of atherosclerosis, due to accumulation of LDL-cholesterol in the blood. Atherosclerosis is the process responsible for the majority of cardiovascular diseases.
Function
LDL receptor complexes are present in clathrin-coated pits (or buds) on the cell surface, which when bound to LDL-cholesterol via adaptin, are pinched off to form clathrin-coated vesicles inside the cell. This allows LDL-cholesterol to be bound and internalized in a process known as endocytosis and prevents the LDL just diffusing around the membrane surface. This occurs in all nucleated cells (not erythrocytes), but mainly in the liver which removes ~70% of LDL from the circulation.
Once the coated vesicle is internalized it will shed its clathrin coat and will fuse with an acidic late endosome. The change in pH causes a conformational change in the receptor that releases the bound LDL particle. The receptors are then either destroyed or they can be recycled via the endocytic cycle back to the surface of the cell where the neutral pH will cause the receptor to revert to its native conformation ready to receive another LDL particle.
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. 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.
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
- ^ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430".
Structure
Gene
The gene coding the LDL receptor 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 EGFP 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. The LDL receptor can be described as a chimeric protein. It is made up of a number of functionally distinct domains that can function independently of each other.
Protein
The N-terminus of the LDL receptor contains a class A domain that is composed of seven sequence repeats (~50% identical) each ~40 amino acids long, with 6 cysteine residues. These ligand binding (LB) regions fold autonomously when synthesised as individual peptides. The cysteine residues form disulfide bonds forming an octahedral lattice, coordinated to a calcium ion, in each repeat. The exact mechanism of interaction between the LB 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 epidermal growth factor (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 a beta-propeller motif (LDL-R class B domain). The EGFP domain has been implicated in release of ligands bound to the receptor. It is thought that a conformational change occurs in the acidic (pH5.0) conditions of the endosome bringing the beta-propeller into contact with ligand-binding repeats 4 and 5.
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.
A membrane spanning domain containing a chain of hydrophobic amino acid residues crosses the plasma membrane of the cell. Inside the cell the C-terminus domain contains a signal sequence that is needed for receptor internalization.
Mutations
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 internalisation of the receptor-ligand complex.
- e.g. "JD" mutant results from a single point mutation in the NPVY domain (C-terminal, cytosolic; Y residue converted to a C, 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).
For a comprehensive list of LDLR variants go to www.ucl.ac.uk/fh Locus specific databases for PCSK9 and LDLRAP1 can also be found via this site.
References
- ^ Yamamoto T, Davis CG, Brown MS, Schneider WJ, Casey ML, Goldstein JL, Russell DW (November 1984). "The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA". Cell 39 (1): 27–38. doi:10.1016/0092-8674(84)90188-0. PMID 6091915.
- ^ Francke U, Brown MS, Goldstein JL (May 1984). "Assignment of the human gene for the low density lipoprotein receptor to chromosome 19: synteny of a receptor, a ligand, and a genetic disease". Proc. Natl. Acad. Sci. U.S.A. 81 (9): 2826–30. doi:10.1073/pnas.81.9.2826. PMC 345163. PMID 6326146.
- ^ Lindgren V, Luskey KL, Russell DW, Francke U (December 1985). "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". Proc. Natl. Acad. Sci. U.S.A. 82 (24): 8567–71. doi:10.1073/pnas.82.24.8567. PMC 390958. PMID 3866240.
- ^ Nykjaer A, Willnow TE (June 2002). "The low-density lipoprotein receptor gene family: a cellular Swiss army knife?". Trends Cell Biol. 12 (6): 273–80. doi:10.1016/S0962-8924(02)02282-1. PMID 12074887.
- ^ "The Nobel Prize in Physiology or Medicine 1985" (Press release). The Royal Swedish Academy of Science. 1985. Retrieved 2010-07-01.
- ^ Brown MS, Goldstein JL (1984). "How LDL Receptors Influence Cholesterol and Atherosclerosis". Scientific American 251 (3): 52–60. doi:10.1038/scientificamerican0984-52. PMID 6390676.
Further reading
- Brown MS, Goldstein JL (1979). "Receptor-mediated endocytosis: insights from the lipoprotein receptor system.". Proc. Natl. Acad. Sci. U.S.A. 76 (7): 3330–7. doi:10.1073/pnas.76.7.3330. PMC 383819. PMID 226968.
- Hobbs HH, Brown MS, Goldstein JL (1993). "Molecular genetics of the LDL receptor gene in familial hypercholesterolemia.". Hum. Mutat. 1 (6): 445–66. doi:10.1002/humu.1380010602. PMID 1301956.
- Fogelman AM, Van Lenten BJ, Warden C, et al. (1989). "Macrophage lipoprotein receptors.". J. Cell Sci. Suppl. 9: 135–49. PMID 2855802.
- Barrett PH, Watts GF (2002). "Shifting the LDL-receptor paradigm in familial hypercholesterolemia: novel insights from recent kinetic studies of apolipoprotein B-100 metabolism.". Atherosclerosis. Supplements 2 (3): 1–4. doi:10.1016/S1567-5688(01)00012-5. PMID 11923121.
- May P, Bock HH, Herz J (2003). "Integration of endocytosis and signal transduction by lipoprotein receptors.". Sci. STKE 2003 (176): PE12. doi:10.1126/stke.2003.176.pe12. PMID 12671190.
- Gent J, Braakman I (2004). "Low-density lipoprotein receptor structure and folding.". Cell. Mol. Life Sci. 61 (19-20): 2461–70. doi:10.1007/s00018-004-4090-3. PMID 15526154.
External links
- Description of LDL receptor pathway at the Brown - Goldstein Laboratory webpage
- LDL Receptor at the US National Library of Medicine Medical Subject Headings (MeSH)
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