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FLASH GENE
Symbol LDLR contributors: mct/pgu - updated : 26-01-2018
HGNC name low density lipoprotein receptor (familial hypercholesterolemia)
HGNC id 6547
Corresponding disease
LDLR hypercholesterolemia, familial
Location 19p13.2      Physical location : 11.200.056 - 11.244.503
Synonym symbol(s) FHC, FH, LDLCQ2
DNA
TYPE functioning gene
STRUCTURE 44.47 kb     18 Exon(s)
10 Kb 5' upstream gene genomic sequence study
regulatory sequence Promoter (TATA box)
text structure sterol independent regulaory element (three repeats + TATA like sequence)
MAPPING cloned Y linked Y status confirmed
Map pter - C3 ,LE - LDLR LDLR - RAB8A - D19S27 - D19S7 ,D19S29 - cen
RNA
TRANSCRIPTS type messenger
identificationnb exonstypebpproduct
ProteinkDaAAspecific expressionYearPubmed
18 - 5292 - 860 - 2006 16920108
18 - 5286 - 858 - 2006 16920108
16 - 4758 - 682 - 2006 16920108
16 - 4788 - 692 - 2006 16920108
17 - 5169 - 819 - 2006 16920108
17 - 4929 - 739 - 2006 16920108
EXPRESSION
Type widely
   expressed in (based on citations)
organ(s)
SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
Digestiveesophagus   moderately
 mouth   highly
Endocrineadrenal gland   highly
 pancreas   moderately
Reproductivemale systemprostate  moderately
Respiratorylung   moderately
 respiratory tracttrachea  highly
 respiratory tractlarynx  moderately
tissue
SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
Muscularstriatumskeletal  
cell lineage
cell lines
fluid/secretion
at STAGE
physiological period embryo, pregnancy
Text umbilical cord
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • three EGF-like domains
  • seven 7 LDL-receptor class A domains
  • six LDL-receptor class B repeats
  • at least 30 AAs in the cytoplasmic domain were required for the LDLR to efficiently exit the ER
  • conjugated GlycoP , ubiquitinated
    HOMOLOGY
    interspecies homolog to rattus Ldlr (77.23 pc)
    homolog to murine Ldlr (78.61 pc)
    Homologene
    FAMILY
  • LDLR family
  • CATEGORY receptor membrane
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,organelle,Golgi
    intracellular,cytoplasm,organelle,endosome
    intracellular,cytoplasm,organelle,lysosome
    text
  • single-pass type I membrane protein
  • newly synthesized LDLR exit the endoplasmic reticulum (ER) as the first step in the secretory pathway
  • LRP6 and LDLR colocalized both on the cell surface and within the cytoplasm
  • basic FUNCTION
  • binding LDL, the major cholesterol-carrying lipoprotein of plasma, and transporting it into cells by endocytosis
  • inflammation-induced disruption of the LDLR pathway was significantly associated with enhanced BMP2 and collagen I expression
  • critical determinant of plasma cholesterol levels that internalizes lipoprotein cargo via clathrin-mediated endocytosis
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS endocytosis transport
    PATHWAY
    metabolism lipid/lipoprotein
    signaling
    a component
  • LDLR-PCSK9 complex is internalized via clathrin-mediated endocytosis and then routed to lysosomes via a mechanism that does not require ubiquitination and is distinct from the autophagy and proteosomal degradation pathways
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • interacting with LDLRAP1
  • interacting with Hepatitis C virus E1 and E2 proteins
  • interacting with PCSK9
  • MYLIP-UBE2D complex is an important determinant of LDLR activity
  • PCSK9 binding to LDLR lead to its intracellular degradation instead of recycling back to cell membrane, and PCSK9-mediated LDLR degradation requires LDLR ubiquitination
  • LRP6 is indispensable for proper LDLR internalization
  • important role of FGF21 and CNPY2 in the regulation of LDLRs
  • PCSK9 is a secreted protein that promotes degradation of cell surface LDL receptors (LDLRs) in selected cell types
  • MYLIP is recruited to the plasma membrane by LDLR, promotes LDLR internalization in the absence of clathrin or caveolae, and facilitates LDLR degradation
  • MYLIP catalyzes the transfer of ubiquitin chains to itself and to the LDLR that do not contain exclusively K48 or K63 linkages
  • PCSK9 is capable of inducing degradation of LRP1, the latter is not an essential factor for LDLR regulation, but the LDLR effectively competes with LRP1 for PCSK9 activity
  • LDLR was shown to mediate clearance of blood coagulation factor VIII (F8) from the circulation
  • binding of WT- ectodomain (ED-LDLR) to pro-PCSK9 in the ER promotes autocatalytic cleavage of PCSK9, and autocatalytically cleaved PCSK9 acts as a chaperone to promote the exit of WT-ED-LDLR from the ER
  • interactors of GCGR, LDLR and TMED2, significantly enhanced glucagon-stimulated glucose production, while YWHAB inhibited glucose production
  • MYLIP is an E3 ubiquitin ligase that targets LDLR for degradation, is a critical determinant of brain APOE metabolism and APP plaque biogenesis
  • binding of PCSK9 to HSP90B1 protects LDLR from degradation likely by preventing early binding of PCSK9 to LDLR within the ER
  • PAQR3 plays a pivotal role in controlling hepatic LDLR degradation and blood LDL-C level via modulating LDLR-PCSK9 interaction
  • cell & other
    REGULATION
    inhibited by MYLIP inducing degradation of LDLR via protein ubiquitination
    repressed by overexpression of PCSK9, through a nonproteasomal mechanism in a post-endoplasmic reticulum compartment
    Other ubiquitination system is involved in PCSK9-induced LDLR degradation
    ASSOCIATED DISORDERS
    corresponding disease(s) LDLR
    related resource Hypercholesterolemia, Familial
    Low Density Lipoprotein Receptor Mutation Database
    Susceptibility
  • to migraine without aura
  • to cerebral infarction
  • Variant & Polymorphism other
  • G142A polymorphism increases the risk of migraine without aura
  • haplotypes rs688 and rs5925 provided preliminary evidence suggesting that genetic polymorphisms of LDLR are associated with cerebral infarction
  • Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • in c-IAP1 null mouse embryonic fibroblasts (MEFs), there is a dramatic decrease in secreted mature PCSK9 protein accompanied by a significant increase in LDLR protein levels compared with matched wild-type MEF cells