LDL receptor
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Location (UCSC) | Chr 19: 11.09 – 11.13 Mb | Chr 9: 21.63 – 21.66 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
The low-density lipoprotein receptor (LDL-R) is a
Structure
Gene
The LDLR gene resides on chromosome 19 at the band 19p13.2 and is split into 18
This gene produces 6
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
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
A third domain of the protein is rich in O-linked
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 bodyneeded 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
Clinical significance
In humans, LDL is directly involved in the development of
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]
- ^ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430".
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000130164 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000032193 - Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 2988123.
- PMID 6326146.
- PMID 3866240.
- ^ a b "LDLR low density lipoprotein receptor [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2016-10-10.
- PMID 12074887.
- ^ "BioGPS - your Gene Portal System". biogps.org. Retrieved 2016-10-10.
- ^ "The Nobel Prize in Physiology or Medicine 1985" (Press release). The Royal Swedish Academy of Science. 1985. Retrieved 2010-07-01.
- PMID 6390676.
- PMID 25487149.
- ^ a b "LDLR - Low-density lipoprotein receptor precursor - Homo sapiens (Human) - LDLR gene & protein". www.uniprot.org. Retrieved 2016-10-10.
- S2CID 25822170.
- S2CID 33590160.
- S2CID 21235282.
- ^ "Low Density Lipoprotein Receptor". LOVD v.1.1.0 - Leiden Open Variation Database. Archived from the original on 2016-01-28. Retrieved 2013-10-17.
- .
- PMID 25222343.
- PMID 19299327.
- S2CID 17712211.
- S2CID 29553611.
- S2CID 34919831.
- PMID 10535997.
- PMID 23589850.
- PMID 27279328.
- S2CID 26062629.
- PMID 27383786.
- PMID 26367797.
- PMID 17334393.
- PMID 24941081.
- S2CID 26995834.
- S2CID 205057802.
- PMID 20686565.
- PMID 25748612.
Further reading
- Brown MS, Goldstein JL (July 1979). "Receptor-mediated endocytosis: insights from the lipoprotein receptor system". Proceedings of the National Academy of Sciences of the United States of America. 76 (7): 3330–7. PMID 226968.
- Hobbs HH, Brown MS, Goldstein JL (1993). "Molecular genetics of the LDL receptor gene in familial hypercholesterolemia". Human Mutation. 1 (6): 445–66. S2CID 5756814.
- Fogelman AM, Van Lenten BJ, Warden C, Haberland ME, Edwards PA (1989). "Macrophage lipoprotein receptors". Journal of Cell Science. Supplement. 9: 135–49. PMID 2855802.
- Barrett PH, Watts GF (March 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. PMID 11923121.
- May P, Bock HH, Herz J (April 2003). "Integration of endocytosis and signal transduction by lipoprotein receptors". Science's STKE. 2003 (176): PE12. S2CID 24468290.
- Gent J, Braakman I (October 2004). "Low-density lipoprotein receptor structure and folding". Cellular and Molecular Life Sciences. 61 (19–20): 2461–70. S2CID 21235282.
External links
- Description of LDL receptor pathway at the Brown - Goldstein Laboratory webpage
- LDL+Receptor at the U.S. National Library of Medicine Medical Subject Headings (MeSH)