LRP6
Protein-coding gene in the species Homo sapiens
From Wikipedia, the free encyclopedia
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.
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.[7][8]
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.[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]
Interactions
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]
Clinical significance
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]