TheLDLR gene resides on chromosome 19 at the band 19p13.2 and is split into 18exons.[8] Exon 1 contains a signal sequence that localises the receptor to theendoplasmic reticulum for transport to the cell surface. Beyond this, exons 2-6 code the ligand binding region; 7-14 code theepidermal 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 6isoforms through alternative splicing.[14]
This protein belongs to the LDLR family and is made up of a number of functionally distinctdomains, including 3 EGF-like domains, 7 LDL-R class A domains, and 6 LDL-R class B repeats.[14]
TheN-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 aclass A repeat orLDL-A, contains roughly 40 amino acids, including 6cysteine residues that formdisulfide 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 theendosome. The exact mechanism of interaction between the class A repeats andligand (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 theYWTD repeat region, which adopts a beta-propeller conformation (LDL-Rclass B domain). It is thought that this region is responsible for the pH-dependent conformational shift that causes bound LDL to be released in theendosome.
A third domain of the protein is rich in O-linkedoligosaccharides 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 theextracellular matrix.
The single transmembrane domain of 22 (mostly) non-polar residues crosses theplasma membrane in a singlealpha helix.
Thecytosolic C-terminal domain contains ~50 amino acids, including a signal sequence important for localizing the receptors toclathrin-coated pits and for triggeringreceptor-mediated endocytosis after binding. Portions of the cytosolic sequence have been found in otherlipoprotein receptors, as well as in more distant receptor relatives.[15][16][17]
Loss-of-function mutations in the gene encoding the LDL receptor are known to cause familial hypercholesterolaemia.
There are 5 broad classes ofmutation 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 theGolgi 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 mildphenotype as receptors are still present on the cell surface (but all must be newly synthesised).[18]
Gain-of-function mutations decrease LDL levels and are a target of research to develop agene therapy to treat refractory hypercholesterolemia.[19]
LDL receptor mediates theendocytosis of cholesterol-rich LDL and thus maintains the plasma level of LDL.[20] This occurs in all nucleated cells, but mainly in theliver which removes ~70% of LDL from the circulation. LDL receptors are clustered inclathrin-coated pits, and coated pits pinch off from the surface to form coated endocytic vesicles that carry LDL into the cell.[21] Afterinternalization, the receptors dissociate from their ligands when they are exposed to lower pH inendosomes. After dissociation, the receptor folds back on itself to obtain a closed conformation and recycles to the cell surface.[22] The rapid recycling of LDL receptors provides an efficient mechanism for delivery of cholesterol to cells.[23][24] It was also reported that by association with lipoprotein in the blood, viruses such ashepatitis C virus,Flaviviridaeviruses andbovine viral diarrheal virus could enter cells indirectly via LDLR-mediated endocytosis.[25] LDLR has been identified as the primary mode of entry for theVesicular stomatitis virus in mice and humans.[26] In addition, LDLR modulation is associated with early atherosclerosis-related lymphatic dysfunction.[27] 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.[28] LDL receptors are translated byribosomes on theendoplasmic reticulum and are modified by theGolgi apparatus before travelling in vesicles to the cell surface.
In humans, LDL is directly involved in the development ofatherosclerosis, which is the process responsible for the majority ofcardiovascular diseases, due to accumulation ofLDL-cholesterol in the blood[citation needed].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.[29][30] 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.[31] Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase and apolipoprotein C-III.[32][33] 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.[34][35]
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 fromstatin 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).[36]
^Nykjaer A, Willnow TE (June 2002). "The low-density lipoprotein receptor gene family: a cellular Swiss army knife?".Trends in Cell Biology.12 (6):273–80.doi:10.1016/S0962-8924(02)02282-1.PMID12074887.
^Yamamoto T, Davis CG, Brown MS, Schneider WJ, Casey ML, Goldstein JL, et al. (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.PMID6091915.S2CID25822170.
^Srivastava RA (December 2023). "New opportunities in the management and treatment of refractory hypercholesterolemia using in vivo CRISPR-mediated genome/base editing".Nutrition, Metabolism and Cardiovascular Diseases.33 (12):2317–2325.doi:10.1016/j.numecd.2023.08.010.PMID37805309.
^Basu SK, Goldstein JL, Anderson RG, Brown MS (May 1981). "Monensin interrupts the recycling of low density lipoprotein receptors in human fibroblasts".Cell.24 (2):493–502.doi:10.1016/0092-8674(81)90340-8.PMID6263497.S2CID29553611.
