Low-density lipoprotein receptor-related protein 6 is a protein that in humans is encoded by the LRP6 gene. [5] [6] LRP6 is a key component of the LRP5/LRP6/Frizzled co-receptor group that is involved in canonical Wnt pathway.
Low-density lipoprotein receptor-related protein 6 is a protein that in humans is encoded by the LRP6 gene. [5] [6] LRP6 is a key component of the LRP5/LRP6/Frizzled co-receptor group that is involved in canonical Wnt pathway.
LRP6 is a transmembrane low-density lipoprotein receptor that shares a similar structure with LRP5. In each protein, about 85% of its 1600-amino-acid length is extracellular. Each has four YWTD β-propeller motifs at the amino terminal end that alternate with four epidermal growth factor (EGF)-like repeats, followed by three LDLR type A repeats. Most extracellular ligands bind to LRP5 and LRP6 at the β-propellers. Each protein has a single-pass, 22-amino-acid transmembrane helix followed by a 207-amino-acid segment that is internal to the cell. [7] [8]
LRP6 acts as a co-receptor with LRP5 and the Frizzled protein family members for transducing signals by Wnt proteins through the canonical Wnt pathway. [8]
A LRP6 mutant lacking the intracellular domain is defective in Wnt signaling [9] while LRP6 mutant lacking the extracellular domain (but anchored on the membrane) are constitutively active. [10]
Canonical WNT signals are transduced through Frizzled receptor and LRP5/LRP6 coreceptor to downregulate GSK3beta (GSK3B) activity not depending on Ser-9 phosphorylation. [11] Reduction of canonical Wnt signals upon depletion of LRP5 and LRP6 results in p120-catenin degradation. [12]
LRP6 is regulated by extracellular proteins in the Dickkopf (Dkk) family (like DKK1 [13] ), sclerostin, R-spondins and members of the cysteine-knot-type protein family. [8]
Common genetic variants of LRP6 have been associated with the risks for hyperlipidemia, [14] atherosclerosis, [15] coronary disease, [16] and late-onset Alzheimer's disease [17] in the general population.
Loss-of-function mutations or LRP6 in humans lead to increased plasma LDL and triglycerides, hypertension, diabetes and osteoporosis. [8] Similarly, mice with a loss-of-function Lrp6 mutation have low bone mass. [18] LRP6 is critical in bone's anabolic response to parathyroid hormone (PTH) treatment, whereas LRP5 is not involved. [18] On the other hand, LRP6 does not appear active in mechanotransduction (bone's response to forces), while LRP5 is critical in that role. [18] Sclerostin, one of the inhibitors of LRP6, is a promising osteocyte-specific Wnt antagonist in osteoporosis clinical trials. [19] [20]
In cellular biology, the Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt, pronounced "wint", is a portmanteau created from the names Wingless and Int-1. Wnt signaling pathways use either nearby cell-cell communication (paracrine) or same-cell communication (autocrine). They are highly evolutionarily conserved in animals, which means they are similar across animal species from fruit flies to humans.
The low-density lipoprotein receptor gene family codes for a class of structurally related cell surface receptors that fulfill diverse biological functions in different organs, tissues, and cell types. The role that is most commonly associated with this evolutionarily ancient family is cholesterol homeostasis. In humans, excess cholesterol in the blood is captured by low-density lipoprotein (LDL) and removed by the liver via endocytosis of the LDL receptor. Recent evidence indicates that the members of the LDL receptor gene family are active in the cell signalling pathways between specialized cells in many, if not all, multicellular organisms.
Frizzled is a family of atypical G protein-coupled receptors that serve as receptors in the Wnt signaling pathway and other signaling pathways. When activated, Frizzled leads to activation of Dishevelled in the cytosol.
Axin-1 is a protein that in humans is encoded by the AXIN1 gene.
Proto-oncogene Wnt-1, or Proto-oncogene Int-1 homolog is a protein that in humans is encoded by the WNT1 gene.
Frizzled-5(Fz-5) is a protein that in humans is encoded by the FZD5 gene.
Frizzled-1(Fz-1) is a protein that in humans is encoded by the FZD1 gene.
Frizzled-6(Fz-6) is a protein that in humans is encoded by the FZD6 gene.
Frizzled-7(Fd-7) is a protein that in humans is encoded by the FZD7 gene.
Frizzled-8(Fz-8) is a protein that in humans is encoded by the FZD8 gene.
Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) also known as G-protein coupled receptor 49 (GPR49) or G-protein coupled receptor 67 (GPR67) is a protein that in humans is encoded by the LGR5 gene. It is a member of GPCR class A receptor proteins. R-spondin proteins are the biological ligands of LGR5. LGR5 is expressed across a diverse range of tissue such as in the muscle, placenta, spinal cord and brain and particularly as a biomarker of adult stem cells in certain tissues.
Low-density lipoprotein receptor-related protein 5 is a protein that in humans is encoded by the LRP5 gene. LRP5 is a key component of the LRP5/LRP6/Frizzled co-receptor group that is involved in canonical Wnt pathway. Mutations in LRP5 can lead to considerable changes in bone mass. A loss-of-function mutation causes osteoporosis pseudoglioma syndrome with a decrease in bone mass, while a gain-of-function mutation causes drastic increases in bone mass.
Dickkopf-related protein 1 is a protein that in humans is encoded by the DKK1 gene.
Secreted frizzled-related protein 1, also known as SFRP1, is a protein which in humans is encoded by the SFRP1 gene.
Protein Wnt-3a is a protein that in humans is encoded by the WNT3A gene.
Protein Wnt-7a is a protein that in humans is encoded by the WNT7A gene.
Dickkopf-related protein 2 is a protein in the Dickkopf family that in humans is encoded by the DKK2 gene.
Kremen protein 1 is a protein that in humans is encoded by the KREMEN1 gene. Kremen1 is conserved in chordates including amphioxus and most vertebrate species. The protein is a type I transmembrane receptor of ligands Dickkopf1, Dickkopf2, Dickkopf3, Dickkopf4, EpCAM and Rspondin1.
Dishevelled (Dsh) is a family of proteins involved in canonical and non-canonical Wnt signalling pathways. Dsh is a cytoplasmic phosphoprotein that acts directly downstream of frizzled receptors. It takes its name from its initial discovery in flies, where a mutation in the dishevelled gene was observed to cause improper orientation of body and wing hairs. There are vertebrate homologs in zebrafish, Xenopus (Xdsh), mice and humans. Dsh relays complex Wnt signals in tissues and cells, in normal and abnormal contexts. It is thought to interact with the SPATS1 protein when regulating the Wnt Signalling pathway.
Dickkopf (DKK) is a family of proteins consisting of five members as of 2020. That is, vertebrates usually contain five genes that are members of the family. The most well-studied is Dickkopf-related protein 1 (DKK1). DKK proteins inhibit the Wnt signaling pathway coreceptors LRP5 and LRP6. They bind with high affinity as ligands to KREMEN1 and KREMEN2, which are transmembrane proteins. DKK proteins have important roles in the development of vertebrates.
Lipids: lipoprotein particle metabolism | ||
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| Apolipoproteins | ||
| Extracellular enzymes | ||
| Lipid transfer proteins | ||
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| ATP-binding cassette transporter | ||