Low density lipoprotein receptor
PDB rendering based on 1ajj.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1AJJ, 1D2J, 1F5Y, 1F8Z, 1HJ7, 1HZ8, 1I0U, 1IJQ, 1LDL, 1LDR, 1N7D, 1XFE, 2FCW, 2KRI, 2LGP, 2W2M, 2W2N, 2W2O, 2W2P, 2W2Q, 3BPS, 3GCW, 3GCX, 3M0C, 3P5B, 3P5C, 3SO6
Identifiers
Symbols	LDLR; FH; FHC; LDLCQ2
External IDs	OMIM: 606945 MGI: 96765 HomoloGene: 55469 ChEMBL: 3311 GeneCards: LDLR Gene
Gene Ontology Molecular function • glycoprotein binding • receptor activity • low-density lipoprotein receptor activity • calcium ion binding • protein binding • very-low-density lipoprotein particle receptor activity Cellular component • lysosome • early endosome • plasma membrane • integral to plasma membrane • coated pit • external side of plasma membrane • endosome membrane • clathrin-coated endocytic vesicle membrane • low-density lipoprotein particle Biological process • lipid metabolic process • transport • endocytosis • receptor-mediated endocytosis • steroid metabolic process • cholesterol metabolic process • positive regulation of triglyceride biosynthetic process • regulation of phosphatidylcholine catabolic process • phospholipid transport • intestinal cholesterol absorption • cholesterol transport • low-density lipoprotein particle clearance • lipoprotein metabolic process • cholesterol homeostasis • small molecule metabolic process • interspecies interaction between organisms • cholesterol import Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	3949	16835
Ensembl	ENSG00000130164	ENSMUSG00000032193
UniProt	P01130	P35951
RefSeq (mRNA)	NM_000527.4	NM_001252658.1
RefSeq (protein)	NP_000518.1	NP_001239587.1
Location (UCSC)	Chr 19: 11.2 – 11.24 Mb	Chr 9: 21.53 – 21.55 Mb
PubMed search	[1]	[2]
This box: view talk edit

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[link]

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[link]

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[link]

Click on genes, proteins and metabolites below to link to respective articles. ^[7]

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Statin Pathway edit

Structure[link]

Gene[link]

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[link]

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[link]

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[link]

Further reading[link]

External links[link]

• Description of LDL receptor pathway at the Brown - Goldstein Laboratory webpage
• LDL+Receptor at the US National Library of Medicine Medical Subject Headings (MeSH)

v t e PDB gallery 1ajj: LDL RECEPTOR LIGAND-BINDING MODULE 5, CALCIUM-COORDINATING   1d2j: LDL RECEPTOR LIGAND-BINDING MODULE 6   1f5y: NMR STRUCTURE OF A CONCATEMER OF THE FIRST AND SECOND LIGAND-BINDING MODULES OF THE HUMAN LDL RECEPTOR   1f8z: NMR STRUCTURE OF THE SIXTH LIGAND-BINDING MODULE OF THE LDL RECEPTOR   1hj7: NMR STUDY OF A PAIR OF LDL RECEPTOR CA2+ BINDING EPIDERMAL GROWTH FACTOR-LIKE DOMAINS, 20 STRUCTURES   1hz8: SOLUTION STRUCTURE AND BACKBONE DYNAMICS OF A CONCATEMER OF EGF-HOMOLOGY MODULES OF THE HUMAN LOW DENSITY LIPOPROTEIN RECEPTOR   1i0u: SOLUTION STRUCTURE AND BACKBONE DYNAMICS OF A CONCATEMER OF EGF-HOMOLOGY MODULES OF THE HUMAN LOW DENSITY LIPOPROTEIN RECEPTOR   1ijq: Crystal Structure of the LDL Receptor YWTD-EGF Domain Pair   1ldl: THREE-DIMENSIONAL STRUCTURE OF A CYSTEINE-RICH REPEAT FROM THE LOW-DENSITY LIPOPROTEIN RECEPTOR   1ldr: SECOND REPEAT OF THE LDL RECEPTOR LIGAND-BINDING DOMAIN   1n7d: Extracellular domain of the LDL receptor   1xfe: Solution structure of the LA7-EGFA pair from the LDL receptor   2fcw: Structure of a Complex Between the Pair of the LDL Receptor Ligand-Binding Modules 3-4 and the Receptor Associated Protein (RAP).

Gary Taubes (born April 30, 1956) is an American science writer.

He is the author of Nobel Dreams (1987), Bad Science: The Short Life and Weird Times of Cold Fusion (1993), and Good Calories, Bad Calories (2007), titled The Diet Delusion (2008) in the UK and Australia.^[1] His book Why We Get Fat: And What to Do About It was released in December 2010. In December 2010 Taubes launched his own blog at GaryTaubes.com to promote the book's release and to respond to critics.

Biography[link]

Born in Rochester, New York, Taubes studied applied physics at Harvard University and aerospace engineering at Stanford University (MS, 1978). After receiving a master's degree in journalism at Columbia University in 1981, Taubes joined Discover magazine as a staff reporter in 1982.^[2] Since then he has written numerous articles for Discover, Science and other magazines. Originally focusing on physics issues, his interests have more recently turned to medicine and nutrition.

Taubes's books have all dealt with scientific controversies. Nobel Dreams takes a critical look at the politics and experimental techniques behind the Nobel Prize-winning work of physicist Carlo Rubbia. Bad Science is a chronicle of the short-lived media frenzy surrounding the Pons-Fleischmann cold fusion experiments of 1989.

His brother, Clifford Henry Taubes, is the William Petschek Professor of Mathematics at Harvard University.^[3]

Dietary science[link]

Gary Taubes on Bookbits radio.

Taubes gained prominence in the low-carb diet debate following the publication of his 2002 New York Times Magazine piece "What if It's All Been a Big Fat Lie?". The article, which questioned the efficacy and health benefits of low-fat diets, was seen as defending the Atkins diet against the medical establishment, and it became extremely controversial. Taubes himself stated: "[E]ven though I knew the article would be the most controversial article the Times Magazine ran all year, [the reaction] still shocked me."^[4] The Center for Science in the Public Interest published a rebuttal to the Times article in its November 2002 newsletter.^[5] According to Taubes: "[T]he CSPI is an advocacy group that has been pushing low-fat diets since the 1970s."^[6]

In 2007, Taubes published his book Good Calories, Bad Calories: Challenging the Conventional Wisdom on Diet, Weight Control, and Disease (published as The Diet Delusion in the UK). This book examined how a hypothesis became dogma and claimed to show how the scientific method was circumvented so a contestable hypothesis could remain unchallenged. The book uses data and studies compiled from dietary research from as early as the 19th century.^[7][8]

Taubes's hypothesis is that the medical community and the federal government of the United States of America have relied upon misinterpreted scientific data on nutrition to build the prevailing paradigm about what constitutes healthful eating. Taubes makes the case that — contrary to the conventional wisdom — it is refined carbohydrates that are responsible for heart disease, diabetes, obesity, cancer, and many other maladies of civilization. In the Epilogue to Good Calories, Bad Calories on page 454, Taubes notes ten "inescapable" conclusions, the first of which is:^[9]

Taubes includes information and studies which indicate that physical exercise increases appetite to a degree that makes it an inefficient tool in weight loss. He tracks the origins of commonly accepted dietary advice and aims to show that information that is filtered to the public often contradicts scientific evidence. On October 19, 2007 Taubes appeared on Larry King Live to discuss his book. Although Taubes has no formal training in nutrition or medicine, his book was praised as "raising interesting and valuable points" by Andrew Weil, a proponent of alternative medicine, while Mehmet Oz and trainer Jillian Michaels who appeared on the same program disagreed with Taubes on many questions.^[10]

The reviews for Good Calories, Bad Calories have varied. George Bray of the Pennington Biomedical Research Center in Louisiana notes in his review that the book "...has much useful information and is well worth reading." but "Obese people clearly eat more than do lean ones."^[11] Taubes, in a letter to the editor in the same journal, clarifies some of the comments made by Bray. Taubes notes, "The hypothesis favored by Bray and a half century of authorities on human obesity is that fat accumulation is fundamentally caused by positive energy balance." Taubes responds, "The alternative hypothesis begins with the fundamental observation that obesity is a disorder of excess fat accumulation and then asks the obvious question, what regulates fat accumulation. This was elucidated by 1965 and has never been controversial. 'Insulin is the principle regulator of fat metabolism'..."^[12]

John Tierney in his New York Times review entitled "Diet and Fat: A Severe Case of Mistaken Consensus", discusses information cascades and the role of Ancel Keys in widely held beliefs related to diet and fat. Tierney quotes Taubes in noting that "the most rigorous meta-analysis of the clinical trials of low-fat diets, published in 2001 by the Cochrane Collaboration, concluded that they had no significant effect on mortality."^[13]

Awards[link]

Taubes has won the Science in Society Journalism Award of the National Association of Science Writers three times and was awarded an MIT Knight Science Journalism Fellowship for 1996-97.^[4] He is a Robert Wood Johnson Foundation independent investigator in health policy.^[14]

See also[link]

• William Banting

References[link]

Publications[link]

• Nobel Dreams: Power, Deceit and the Ultimate Experiment. Random House. 1986. ISBN 978-0-394-54503-5. 
• Bad Science: The Short Life and Weird Times of Cold Fusion. Random House. 1993. ISBN 978-0-394-58456-0. 
• Epidemiology Faces Its Limits, Science, July 1995.
• Nobel Gas, Slate, October 11, 1997.
• The Soft Science of Dietary Fat, Science, March 2001.
• What if It's All Been a Big Fat Lie?, New York Times Magazine, July 7, 2002.
• Do We Really Know What Makes Us Healthy?, New York Times, September 17, 2007.
• Good Calories, Bad Calories: Challenging the Conventional Wisdom on Diet, Weight Control, and Disease. Knopf. 2007. ISBN 978-1-4000-4078-0.  (Also published as The Diet Delusion ISBN 978-0-09-189141-1)
• Why We Get Fat: And What to Do About It. 2010. 
• Is Sugar Toxic?. The New York Times, April 13, 2011.

External links[link]

• (Link is dead) Webcast of Lecture by Gary Taubes at University of California, Berkeley -- "The Quality of Calories: What Makes Us Fat and Why Nobody Seems to Care"
• Webcast of Lecture by Gary Taubes at Stevens Institute of Technology, Center for Science Writings, Hoboken, NJ, USA, 2/6/2008 -- "Big Fat Lies"
• Article by Gary Taubes questioning the efficacy of exercise in weight loss -- "We Can't Work It Out"
• Excerpt from Good Calories, Bad Calories and NPR interview -- "Not All Calories Are Created Equal, Author Says".
• Interview with Gary Taubes by Knight Fellowships at MIT
• Interview with Gary Taubes by John Horgan (Stevens Center for Science Writing, Cross-check): "Science Saturday: Why We Get Fat"
• Interview with Gary Taubes by Aaron McCloud, Seattle, 2012, and the Interview Transcript

John Yudkin (8 August 1910 - 12 July 1995) was a British physiologist and scientist. He became internationally famous with his book Pure, White and Deadly (published in 1972), which was also published in German, Finnish, and in a Swedish translation Rent, vitt, livsfarligt.

Biography[link]

He was raised in London in a Jewish family that had fled the Russian pogroms of 1905. His father died when John was seven years old. His mother had to bring up five sons in very difficult circumstances. In 1933 he married Milly Himmelweit, who had fled from Germany. They had three sons and their marriage lasted 60 years.

He wrote his PhD under the guidance of Marjory Stephenson, a bacteriologist. He was very interested in the science of nutrition, but to work in this field of research he had to become a medical doctor (physician). In 1938 he undertook research into vitamin A and riboflavin at the Dunn Nutrition Laboratory. He examined the link between sugar and various degenerative illnesses. During World War II he served as a military physician in West Africa and was busy with further studies.

In 1945 he was appointed Professor of Physiology at the University of London. With his help the Bachelor's degree and Master's degree in nutrition were established at the College and the University. He advised the government of the young state of Israel on nutrition matters and was an energetic governor of the Hebrew University of Jerusalem.

Since 1957 he showed that the consumption of sugar and refined sweeteners is closely associated with coronary heart disease and type 2 diabetes. Studies he conducted on sugars indicated that they raised blood triglycerides and insulin levels.^[1]

He is lauded by Dr. Robert H. Lustig in his UCTV lecture, "Sugar: The Bitter Truth", which may be viewed on YouTube.^[2]

John Yudkin was Professor of Nutrition and Dietetics in the University of London from 1954 to 1971 and later became Emeritus Professor. Born in 1910 he proceeded from Christ's College, Cambridge, to the London Hospital and later did research work in the Biochemical Laboratory and the Nutritional Laboratory at Cambridge, where he was also Director of Medical Studies at Christ's College. His degrees include M.A., M.D. (Cantab), B.Sc. (Lond.), M.R.C.P., and F.R.I.C. From 1945 to 1954 he was Professor of Physiology at Queen Elizabeth College, University of London. He has published many articles on biochemistry and nutrition.

John Yudkin was an early advocate of low carbohydrate diets later to be popularised by Robert Atkins in the USA.

Publications[link]

• John Yudkin: Medicine and medical education in the new China, 1958
• John Yudkin, G.M. Chappell: The Slimmer's Cook Book. Penguin Handbooks, 1963.
• John Yudkin: Pure, White and Deadly. Davis-Poynter Ltd, 1972.
• John Yudkin: The New Facts About the Sugar You Eat As a Cause of Heart Disease, Diabetes, and Other Killers. Peter H. Wyden, Publishing 1972
• John Yudkin: Sweet and Dangerous, New York: Bantam Books, 1972
• John Yudkin: The Penguin Encyclopaedia of Nutrition. Harmondsworth, Middlesex, England: Penguin Books; New York: Viking Penguin, 1985.
• John Yudkin: This Slimming Business, 1970.

References[link]