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| LDLR | |
|---|---|
| Name | Low-density lipoprotein receptor |
| Organism | Homo sapiens |
| Uniprot | P01130 |
| Location | Plasma membrane, endosome |
LDLR The low-density lipoprotein receptor is a cell-surface glycoprotein that mediates uptake of circulating lipoprotein particles, influencing systemic cholesterol homeostasis and cardiovascular risk. Discovered through studies linking familial hypercholesterolemia to defective cellular uptake, the receptor has been central to research in lipid biology, molecular genetics, and therapeutic development involving monoclonal antibodies and small molecules. Major contributions to understanding LDLR came from investigators associated with institutions such as Harvard University, Johns Hopkins University, Massachusetts Institute of Technology, Stanford University and clinical networks including the American Heart Association and World Health Organization.
The receptor is a single-chain transmembrane protein with multiple modular domains characterized by ligand-binding repeats, an epidermal growth factor (EGF)-like region, a beta-propeller domain, a transmembrane helix and a cytoplasmic tail containing an endocytic signal; structural insights were refined using techniques at facilities like the European Molecular Biology Laboratory, Max Planck Society, Royal Society, Cold Spring Harbor Laboratory and Wellcome Trust-funded centers. High-resolution crystallography and cryo-electron microscopy studies performed at Diamond Light Source, Brookhaven National Laboratory, Lawrence Berkeley National Laboratory, Argonne National Laboratory and National Institutes of Health cores revealed calcium-dependent ligand binding and conformational changes shared with receptors in the same family studied by teams at University of Cambridge, University of Oxford, Yale University and University of California, San Francisco. Post-translational modifications such as N-linked glycosylation, disulfide bond formation and proteolytic processing were mapped using workflows developed at European Synchrotron Radiation Facility, Riken, Institute Pasteur and Karolinska Institutet.
LDLR mediates receptor-mediated endocytosis of apolipoprotein B- and apolipoprotein E-containing lipoproteins, a pathway explored in landmark experiments at Rockefeller University, Columbia University, University of Pennsylvania, University of Chicago and Duke University that linked cellular uptake to plasma low-density lipoprotein levels. The receptor operates within the endosomal-lysosomal system alongside trafficking regulators studied at National Cancer Institute, Salk Institute, Broad Institute, European Bioinformatics Institute and Instituto Nacional de Salud Pública to control intracellular cholesterol sensing, influencing transcriptional programs governed by factors first described in association with Nobel Prize-winning labs and collaborative groups at ETH Zurich and University of Geneva. Crosstalk with lipoprotein remodeling pathways investigated at The Rockefeller University Hospital, Mayo Clinic, Cleveland Clinic and John Radcliffe Hospital integrates LDLR activity with systemic lipid transport networks characterized by epidemiological consortia including Framingham Heart Study and INTERHEART.
Mutations in the receptor gene were identified in pedigrees studied by clinical genetics groups at Boston Children's Hospital, Great Ormond Street Hospital, Royal Free Hospital and research centers like Wellcome Sanger Institute and Broad Institute, with allele-specific effects mapped using genomic platforms at Illumina, Baylor College of Medicine, The Jackson Laboratory and Human Genome Project-era collaborations. Transcriptional regulation involves sterol regulatory element-binding proteins and co-regulators characterized by labs at Howard Hughes Medical Institute, Imperial College London, Max Planck Institute for Heart and Lung Research, University of Basel and University of Toronto, while post-transcriptional control by microRNAs and RNA-binding proteins was advanced in studies from Cold Spring Harbor Laboratory, Karolinska Institutet, University of Copenhagen and National University of Singapore. Population genetics and variant interpretation are informed by databases and consortia such as 1000 Genomes Project, Exome Aggregation Consortium, ClinVar and collaborative initiatives led by European Society of Cardiology and American College of Medical Genetics and Genomics.
Defective LDLR function underlies autosomal dominant familial hypercholesterolemia identified in clinical series from St Thomas' Hospital, Hopkins Lipid Clinic, Mount Sinai Hospital, Royal Melbourne Hospital and multicenter registries coordinated with European Atherosclerosis Society and International Atherosclerosis Society. Reduced receptor activity contributes to premature atherosclerosis documented in cohorts from Framingham Heart Study, CARDIA Study, MESA Study and outcome trials run by organizations like National Heart, Lung, and Blood Institute, European Medicines Agency and Food and Drug Administration. Genetic screening, cascade testing and lipid management protocols developed by National Lipid Association, American College of Cardiology, National Health Service and specialty centers inform diagnosis and risk stratification in affected families tracked by registries at University College London and Ottawa Heart Institute.
Loss-of-function variants impair receptor-mediated clearance of apoB-containing particles, increasing plasma LDL cholesterol and promoting foam cell formation, atherosclerotic plaque development and ischemic events investigated by vascular biology groups at John Radcliffe Hospital, St Bartholomew's Hospital, Mayo Clinic, Cleveland Clinic Foundation and translational programs affiliated with Wellcome Trust Sanger Institute and Cambridge Biomedical Campus. Cellular stress responses, endoplasmic reticulum-associated degradation and altered trafficking involving proteins characterized at Max Delbrück Center, Francis Crick Institute, Institut Curie and Monash University exacerbate receptor deficiency phenotypes. Animal models and interventional studies conducted at The Jackson Laboratory, European Molecular Biology Laboratory and institutional vivaria underpin mechanistic links to thrombosis and vascular inflammation studied in consortia including TRANSFORM-UK and multicenter cardiovascular research networks.
LDLR function is a principal target of lipid-lowering strategies developed by pharmaceutical and academic collaborations including teams at Pfizer, Regeneron Pharmaceuticals, Amgen, Novartis and AstraZeneca; approaches include statins, PCSK9 inhibitors, antisense oligonucleotides and small molecules tested in trials coordinated by European Medicines Agency, Food and Drug Administration, ClinicalTrials.gov registries and cooperative groups like European Atherosclerosis Society and American Heart Association. PCSK9 inhibitors, monoclonal antibodies and RNA-based therapeutics enhance receptor recycling or expression, with pivotal trials run at centers such as Brigham and Women's Hospital, Mayo Clinic, Cleveland Clinic and international research networks shaping guideline recommendations from American College of Cardiology and European Society of Cardiology. Emerging gene-editing and gene-replacement therapies evaluated in translational programs at Broad Institute, Salk Institute, Harvard Medical School, Stanford Medicine and regulatory pathways overseen by Food and Drug Administration and European Medicines Agency aim to restore receptor function in severe inherited cases.
Category:Human proteins