LDL receptor
Encyclopedia
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 is encoded by the LDLR gene
. It belongs to the Low density lipoprotein receptor gene family
.
Brown and Goldstein
won a Nobel Prize for their identification of the Low Density Lipoprotein (LDL) receptor in 1985 while they were studying familial hypercholesterolemia
.
, due to accumulation of LDL-cholesterol in the blood. Atherosclerosis is the process responsible for the majority of cardiovascular diseases.
-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.
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.
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.
of the LDL receptor.
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.
Endocytosis
Endocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
of cholesterol-rich LDL. It is a cell-surface receptor that recognizes the apoprotein
Apoprotein
Apoprotein can refer to:*Apoenzyme, the protein part of an enzyme without its characteristic prosthetic group.*Apolipoprotein, a lipid-binding protein that is a constituent of the plasma lipoprotein....
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 is encoded by the LDLR gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. It belongs to the Low density lipoprotein receptor gene family
Low density lipoprotein receptor gene family
The low density lipoprotein receptor gene family code for a class of structurally closely related cell surface receptors that fulfill diverse biological functions in different organs, tissues, and cell types. The role that is most commonly associated with this evolutionarily ancient family is...
.
Brown and Goldstein
Joseph L. Goldstein
Joseph L. Goldstein from Kingstree, South Carolina is a Nobel Prize winning biochemist and geneticist, and a pioneer in the study of cholesterol metabolism.-Biography:...
won a Nobel Prize for their identification of the Low Density Lipoprotein (LDL) receptor in 1985 while they were studying familial hypercholesterolemia
Familial hypercholesterolemia
Familial hypercholesterolemia is a genetic disorder characterized by high cholesterol levels, specifically very high levels of low-density lipoprotein , in the blood and early cardiovascular disease...
.
Clinical significance
LDL is directly involved in the development of atherosclerosisAtherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
, 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 clathrinClathrin
Clathrin is a protein that plays a major role in the formation of coated vesicles. Clathrin was first isolated and named by Barbara Pearse in 1975. It forms a triskelion shape composed of three clathrin heavy chains and three light chains. When the triskelia interact they form a polyhedral lattice...
-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
Endocytosis
Endocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
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
Endocytic cycle
Most animal cells take up portions of their surface plasma membranes in a process called endocytosis. The main route of endocytosis is the coated pit, which buds into a cell to form a cytoplasmic vesicle — a clathrin-coated vesicle. The membrane so internalised is processed in a series of...
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
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
and are modified by the Golgi apparatus
Golgi apparatus
The Golgi apparatus is an organelle found in most eukaryotic cells. It was identified in 1898 by the Italian physician Camillo Golgi, after whom the Golgi apparatus is named....
before travelling in vesicles to the cell surface.
Gene
The geneGene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
coding the LDL receptor is split into 18 exons. Exon 1 contains a signal sequence that localises the receptor to the endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
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
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
. It is made up of a number of functionally distinct domains
Protein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
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 cysteineCysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
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
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
(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
Epidermal growth factor
Epidermal growth factor or EGF is a growth factor that plays an important role in the regulation of cell growth, proliferation, and differentiation by binding to its receptor EGFR...
(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
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
.
A membrane spanning domain containing a chain of hydrophobic amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
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 mutationMutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
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 phenotypePhenotypeA phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
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.