Low-density lipoprotein receptor-related protein 6 is a protein that in humans is encoded by the LRP6 gene. LRP6 is a key component of the LRP5/LRP6/Frizzled co-receptor group that is involved in canonical Wnt pathway.

Structure

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.

Function

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. A LRP6 mutant lacking the intracellular domain is defective in Wnt signaling while LRP6 mutant lacking the extracellular domain (but anchored on the membrane) are constitutively active.

Interactions

Canonical WNT signals are transduced through Frizzled receptor and LRP5/LRP6 coreceptor to downregulate GSK3beta (GSK3B) activity not depending on Ser-9 phosphorylation. Reduction of canonical Wnt signals upon depletion of LRP5 and LRP6 results in p120-catenin degradation. LRP6 is regulated by extracellular proteins in the Dickkopf (Dkk) family (like DKK1 ), sclerostin, R-spondins and members of the cysteine-knot-type protein family.

Clinical significance

Common genetic variants of LRP6 have been associated with the risks for hyperlipidemia, atherosclerosis, coronary disease, and late-onset Alzheimer's disease in the general population. 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 response to parathyroid hormone (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.