Low-density lipoprotein receptor-related protein 6 is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

that in humans is encoded by the ''LRP6''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

. LRP6 is a key component of the LRP5/LRP6/

Frizzled 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. Species distribution Fr ...

co-receptor group that is involved in canonical Wnt pathway.

Structure

LRP6 is a transmembrane low-density

lipoprotein A lipoprotein is a biochemical assembly whose primary function is to transport hydrophobic lipid (also known as fat) molecules in water, as in blood plasma or other extracellular fluids. They consist of a triglyceride and cholesterol center, ...

receptor Receptor may refer to: *Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a n ...

that shares a similar structure with LRP5. In each protein, about 85% of its 1600-

amino-acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ami ...

length is extracellular. Each has four β-propeller motifs at the

amino terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...

end that alternate with four

epidermal growth factor Epidermal growth factor (EGF) is a protein that stimulates cell growth and differentiation by binding to its receptor, EGFR. Human EGF is 6-k Da and has 53 amino acid residues and three intramolecular disulfide bonds. EGF was originally de ...

(EGF)-like repeats. Most extracellular ligands bind to LRP5 and LRP6 at the β-propellers. Each protein has a single-pass, 22-amino-acid segment that crosses the cell membrane and a 207-amino-acid segment that is internal to the cell.

Function

LRP6 acts as a co-receptor with LRP5 and the

protein family members for transducing signals by Wnt proteins through the canonical Wnt pathway.

Interactions

Canonical

WNT signals 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 is a portmanteau created from the names Wingless and Int-1. Wnt signaling p ...

are transduced through

receptor and LRP5/LRP6 coreceptor to downregulate GSK3beta ( GSK3B) activity not depending on Ser-9

phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...

. Reduction of canonical Wnt signals upon depletion of LRP5 and LRP6 results in p120-

catenin Catenins are a family of proteins found in complexes with cadherin cell adhesion molecules of animal cells. The first two catenins that were identified became known as α-catenin and β-catenin. α-Catenin can bind to β-catenin and can also bind ...

degradation. LRP6 is regulated by extracellular proteins in the

Dickkopf Dickkopf (DKK) is a family of proteins consisting of five members as of 2020. 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 ...

(Dkk) family (like DKK1),

sclerostin Sclerostin is a protein that in humans is encoded by the ''SOST'' gene. Sclerostin is a secreted glycoprotein with a C-terminal cysteine knot-like (CTCK) domain and sequence similarity to the DAN (differential screening-selected gene aberrative ...

, R-spondins and members of the cysteine-knot-type protein family.

Clinical significance

Loss-of-function mutations or LRP6 in humans lead to increased plasma LDL and triglycerides, hypertension, diabetes and osteoporosis. Similarly, mice with a loss-of-function Lrp6 mutation have low bone mass. LRP6 is critical in bone's

anabolic Anabolism () is the set of metabolic pathways that construct molecules from smaller units. These reactions require energy, known also as an endergonic process. Anabolism is the building-up aspect of metabolism, whereas catabolism is the breakin ...

response to

parathyroid hormone Parathyroid hormone (PTH), also called parathormone or parathyrin, is a peptide hormone secreted by the parathyroid glands that regulates the serum calcium concentration through its effects on bone, kidney, and intestine. PTH influences bone ...

(PTH) treatment, whereas LRP5 is not involved. On the other hand, LRP6 does not appear active in mechanotransduction (bone's response to forces), while LRP5 is critical in that role. Sclerostin, one of the inhibitors of LRP6, is a promising osteocyte-specific Wnt antagonist in osteoporosis clinical trials.

Structure

Function

Interactions

Clinical significance

References

Further reading