Parameters of LRP5 from a Structural and Molecular Perspective

Abstract

LRP5, along with LRP6 and their Drosophila homolog, Arrow, constitute a novel subclass of the LDL receptor superfamily. The arrangement of structural motifs in these receptors is different from the other members of the superfamily, and only recently have we begun to understand the functional importance of human LRP5 (and LRP6). Whole genome positional cloning studies have identified a number of mutations in LRP5 that underlie inherited human diseases/phenotypes, particularly those involving the skeleton and the eye. A number of studies have illustrated the importance of Lrp5/6/Arrow as a co-receptor with Frizzled for the Wnt proteins and their critical role in the regulation of the Wnt/beta-catenin signaling pathway. The cataloging of these human mutations, in combination with engineered mutations in mice and other studies involving gene/protein modifications, has led to a better understanding of the function of the various domains in LRP5/6. In this review, we discuss a number of studies that have revealed a wide variety of protein-protein interactions that occur with the various structural motifs in the Lrp5 protein. Ultimately, these interactions regulate the activity of the Wnt/beta-catenin signaling pathway and the role it plays in processes such as bone mass accrual and vision.

Structure-based mutation analysis shows the importance of LRP5 β-propeller 1 in modulating Dkk1-mediated inhibition of Wnt signaling

“…In contrast, rationally designed missense mutations (G479V, G781V and Q1087V) in G171 equivalent sites in blade 4 of β-propellers 2, 3 or 4 did not result in the suppression of Dkk1 function even though all of these variants could signal in response to Wnt1. This indicates that among the four β-propellers, β-propeller 1 plays an important role in mediating resistance to Dkk1 function in vitro and in turn suggests that LRP5 β-propeller 1 variants in addition to G171V could result in the high bone mass phenotype in vivo (Johnson and Summerfield, 2005). This hypothesis is supported by recent reports indicating that several LRP5 β-propeller 1 mutations (D111Y, G171R, A214T, A214V, A242T and T243I) have been identified from patients with increased bone density, and that these LRP5 variants activate Wnt signaling by relieving Dkk1-mediated inhibition in an in vitro TCF signaling assay (Van Wesenbeeck et al, 2003;Ai et al, 2005b;Koay and Brown, 2005;Kwee et al, 2005).…”

Diseases of Wnt signaling

“…Remarkably, what were once thought to be seemingly disparate bone disorders based on their clinical characterization are now known to have an underlying common molecular basis that could not have been predicted when they were first clinically described decades ago [63]. Our molecular dissection of these bone diseases has revealed a complex pattern of regulation of key signaling pathways and interaction between bone cells that can now be explained at an ever increasing finer level of detail.…”

“…The catalog of mutations in LRP5 that give rise to the human disease OsteoporosisPseudoglioma Syndrome (OPPG) is constantly growing (see reviews [63] and [85]). This disease is characterized by a juvenile onset osteoporosis and congenital or early infancyonset blindness.…”

Characterization of the Interaction of Sclerostin with the Low Density Lipoprotein Receptor-related Protein (LRP) Family of Wnt Co-receptors

“…1A) (9). Both of these receptors have cytoplasmic domains of ϳ200 amino acids, which contain five copies of a PPPS/TPXS signaling motif that is involved in the recruitment of axin and the inhibition of glycogen synthase kinase 3␤ (GSK3␤), a kinase that phosphorylates ␤-catenin and targets it for proteasomal destruction (2,9,10). The folding of both LRP5/6 is assisted by a specialized chaperone protein called MESD (mesoderm development) (11).…”