LDL receptor

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LDLR
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LDLR
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl
UniProt
RefSeq (mRNA)

NM_001252658
NM_001252659
NM_010700

RefSeq (protein)

NP_000518
NP_001182727
NP_001182728
NP_001182729
NP_001182732

NP_001239587
NP_001239588
NP_034830

Location (UCSC)Chr 19: 11.09 – 11.13 MbChr 9: 21.63 – 21.66 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

The low-density lipoprotein receptor (LDL-R) is a

epithelial cells and adrenal gland and cortex tissue.[10]

Michael S. Brown and Joseph L. Goldstein were awarded the 1985 Nobel Prize in Physiology or Medicine for their identification of LDL-R[11] and its relation to cholesterol metabolism and familial hypercholesterolemia.[12] 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.[13]

Structure

Gene

The LDLR gene resides on chromosome 19 at the band 19p13.2 and is split into 18

exons.[8] 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.[14]

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.[14]

The

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

.

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.[15][16][17]

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:

  • 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).[18]

Gain-of-function mutations decrease LDL levels and are a target of research to develop a gene therapy to treat refractory hypercholesterolemia.[19]

Function

LDL receptor mediates the

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

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.[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]

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).[36]

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

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Statin_Pathway_WP430go to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to article
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Statin_Pathway_WP430go to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to article
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Statin Pathway edit
  1. ^ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430".

References

Further reading

External links

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