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Low-density lipoprotein receptor (LDLR) family orchestrates cholesterol homeostasis.

Go GW, Mani A - Yale J Biol Med (2012)

Bottom Line: The LDLR family of proteins is involved in lipoproteins trafficking.LRP6 is a unique member of this family for its function as a co-receptor for Wnt signal transduction.The role of these receptor proteins in pathogenesis of diverse metabolic risk factors is emerging, rendering them targets of novel therapeutics for metabolic syndrome and atherosclerosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.

ABSTRACT
The LDLR family of proteins is involved in lipoproteins trafficking. While the role of LDLR in cardiovascular disease has been widely studied, only recently the role of other members of the LDLR proteins in lipoprotein homeostasis and atherosclerosis has emerged. LDLR, VLDLR, and LRPs bind and internalize apoE- and apoB-containing lipoprotein, including LDL and VLDL, and regulate their cellular uptake. LRP6 is a unique member of this family for its function as a co-receptor for Wnt signal transduction. The work in our laboratory has shown that LRP6 also plays a key role in lipoprotein and TG clearance, glucose homoeostasis, and atherosclerosis. The role of these receptor proteins in pathogenesis of diverse metabolic risk factors is emerging, rendering them targets of novel therapeutics for metabolic syndrome and atherosclerosis. This manuscript reviews the physiological role of the LDLR family of proteins and describes its involvement in pathogenesis of hyperlipidemia and atherosclerosis.

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Related in: MedlinePlus

Low-density lipoprotein receptor family. LDLR is the patriarchof the LDLR family. Members of the LDLR family share common structuralmotifs: LDLR type A repeats (responsible for binding of ligands), epidermalgrowth factor (EGF)-like domain (involved in pH-dependent release of ligandsin endosome), transmembrane anchor, and cytoplasmic domain (binding of NPxYand ARH mediates clustering of the receptors into clathrin coated pit).LDLR, VLDLR, and LRP8 (ApoER2) additionally contain o-link sugar domainoutside the plasma membrane and NPxY motif in the cytoplasmic domain. LRP1and LRP2 have relatively large extracellular domains. LRP5/6 has PPPSP motifin cytoplasmic domain.
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Figure 1: Low-density lipoprotein receptor family. LDLR is the patriarchof the LDLR family. Members of the LDLR family share common structuralmotifs: LDLR type A repeats (responsible for binding of ligands), epidermalgrowth factor (EGF)-like domain (involved in pH-dependent release of ligandsin endosome), transmembrane anchor, and cytoplasmic domain (binding of NPxYand ARH mediates clustering of the receptors into clathrin coated pit).LDLR, VLDLR, and LRP8 (ApoER2) additionally contain o-link sugar domainoutside the plasma membrane and NPxY motif in the cytoplasmic domain. LRP1and LRP2 have relatively large extracellular domains. LRP5/6 has PPPSP motifin cytoplasmic domain.

Mentions: The LDLR family comprises a group of endocytic receptors on the cell surface, whichbind and internalize extracellular ligands, including lipoproteins, exotoxins, andlipid-carrier complexes [6].Members of the LDLR family are structurally and functionally related to LDLR, whichis the patriarch of the entire family. Proteins of the LDLR family sharestructurally common motifs (Figure 1): LDLRtype A repeats, epidermal growth factor (EGF)-like domain, transmembrane anchor,and, in certain instances, cytoplasmic domain. LDLR and VLDLR additionally containo-link sugar domain, located just outside of the plasma membrane. LRP1 and LRP2(megalin) have relatively large extracellular domains [7]. LDLR type A repeats are localized to a region atNH2-terminal and responsible for binding of ligands, including apoB-100- andapoE-containing lipoprotein. EGF-like precursor contains multiple EGF repeats alongwith a β-propeller domain and is involved in pH-dependent dissociation ofligand-receptor complex. Transmembrane domain helps anchor the receptors to themembrane. Cytoplasmic domain contains NPxY (Asn-Pro-any amino acid(x)-Tyr)-containing domain or PPPSP motif (Pro-Pro-Pro-Ser-Pro) [7] and is involved in the targeting ofreceptors to coated pits and signal transduction. Differences in position and numberof each domain create the diversity in LDLR family members. To date, numerousmembers of the LDLR family are reported that participate in a wide range ofphysiological processes [8].In particular, LDLR, VLDLR, LRP5/6, LRP1, and LRP2 play a pivotal role incholesterol homeostasis and lipid metabolism [9-13].


Low-density lipoprotein receptor (LDLR) family orchestrates cholesterol homeostasis.

Go GW, Mani A - Yale J Biol Med (2012)

Low-density lipoprotein receptor family. LDLR is the patriarchof the LDLR family. Members of the LDLR family share common structuralmotifs: LDLR type A repeats (responsible for binding of ligands), epidermalgrowth factor (EGF)-like domain (involved in pH-dependent release of ligandsin endosome), transmembrane anchor, and cytoplasmic domain (binding of NPxYand ARH mediates clustering of the receptors into clathrin coated pit).LDLR, VLDLR, and LRP8 (ApoER2) additionally contain o-link sugar domainoutside the plasma membrane and NPxY motif in the cytoplasmic domain. LRP1and LRP2 have relatively large extracellular domains. LRP5/6 has PPPSP motifin cytoplasmic domain.
© Copyright Policy - open access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3313535&req=5

Figure 1: Low-density lipoprotein receptor family. LDLR is the patriarchof the LDLR family. Members of the LDLR family share common structuralmotifs: LDLR type A repeats (responsible for binding of ligands), epidermalgrowth factor (EGF)-like domain (involved in pH-dependent release of ligandsin endosome), transmembrane anchor, and cytoplasmic domain (binding of NPxYand ARH mediates clustering of the receptors into clathrin coated pit).LDLR, VLDLR, and LRP8 (ApoER2) additionally contain o-link sugar domainoutside the plasma membrane and NPxY motif in the cytoplasmic domain. LRP1and LRP2 have relatively large extracellular domains. LRP5/6 has PPPSP motifin cytoplasmic domain.
Mentions: The LDLR family comprises a group of endocytic receptors on the cell surface, whichbind and internalize extracellular ligands, including lipoproteins, exotoxins, andlipid-carrier complexes [6].Members of the LDLR family are structurally and functionally related to LDLR, whichis the patriarch of the entire family. Proteins of the LDLR family sharestructurally common motifs (Figure 1): LDLRtype A repeats, epidermal growth factor (EGF)-like domain, transmembrane anchor,and, in certain instances, cytoplasmic domain. LDLR and VLDLR additionally containo-link sugar domain, located just outside of the plasma membrane. LRP1 and LRP2(megalin) have relatively large extracellular domains [7]. LDLR type A repeats are localized to a region atNH2-terminal and responsible for binding of ligands, including apoB-100- andapoE-containing lipoprotein. EGF-like precursor contains multiple EGF repeats alongwith a β-propeller domain and is involved in pH-dependent dissociation ofligand-receptor complex. Transmembrane domain helps anchor the receptors to themembrane. Cytoplasmic domain contains NPxY (Asn-Pro-any amino acid(x)-Tyr)-containing domain or PPPSP motif (Pro-Pro-Pro-Ser-Pro) [7] and is involved in the targeting ofreceptors to coated pits and signal transduction. Differences in position and numberof each domain create the diversity in LDLR family members. To date, numerousmembers of the LDLR family are reported that participate in a wide range ofphysiological processes [8].In particular, LDLR, VLDLR, LRP5/6, LRP1, and LRP2 play a pivotal role incholesterol homeostasis and lipid metabolism [9-13].

Bottom Line: The LDLR family of proteins is involved in lipoproteins trafficking.LRP6 is a unique member of this family for its function as a co-receptor for Wnt signal transduction.The role of these receptor proteins in pathogenesis of diverse metabolic risk factors is emerging, rendering them targets of novel therapeutics for metabolic syndrome and atherosclerosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.

ABSTRACT
The LDLR family of proteins is involved in lipoproteins trafficking. While the role of LDLR in cardiovascular disease has been widely studied, only recently the role of other members of the LDLR proteins in lipoprotein homeostasis and atherosclerosis has emerged. LDLR, VLDLR, and LRPs bind and internalize apoE- and apoB-containing lipoprotein, including LDL and VLDL, and regulate their cellular uptake. LRP6 is a unique member of this family for its function as a co-receptor for Wnt signal transduction. The work in our laboratory has shown that LRP6 also plays a key role in lipoprotein and TG clearance, glucose homoeostasis, and atherosclerosis. The role of these receptor proteins in pathogenesis of diverse metabolic risk factors is emerging, rendering them targets of novel therapeutics for metabolic syndrome and atherosclerosis. This manuscript reviews the physiological role of the LDLR family of proteins and describes its involvement in pathogenesis of hyperlipidemia and atherosclerosis.

Show MeSH
Related in: MedlinePlus