Wnt Antagonists Bind through a Short Peptide to the First β-Propeller Domain of LRP5/6

Bourhis, E. Le; Wang, Weiru; Tam, Christine; Hwang, Ji-Young; Zhang, Yingnan; Spittler, Didier; Huang, Oscar W.; Gong, Yan; Estevez, Alberto; Zilberleyb, Inna; Rougé, Lionel; Chiu, Cecilia; Wu, Yan; Costa, Mike; Hannoush, Rami N.; Franke, Yvonne; Cochran, Andrea G.

doi:10.1016/j.str.2011.07.005

Cited by 151 publications

(214 citation statements)

References 59 publications

(98 reference statements)

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“…5E). The ability of the peptides used in this study to inhibit Wnt1 signaling was unexpected in the light of a report by Bourhis et al (36), suggesting that similar peptides did not inhibit Wnt9B binding to LRP6 (which, similar to Wnt1, has been proposed to bind to the first propeller of LRP5/6). To investigate this further, we attempted to stimulate canonical Wnt signaling in our reporter cell line with Wnt9B.…”

Section: Asn-93 Of Sclerostin Plays Key Role In Its Ability To Interamentioning

confidence: 53%

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

Holdsworth

Slocombe

Doyle

et al. 2012

Journal of Biological Chemistry

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Background: Sclerostin, an inhibitor of Wnt signaling, binds to the ␤-propeller domain-containing Wnt co-receptors LRP6 and LRP4. Results: An NXI motif in sclerostin mediates interactions with LRP6 (but not LRP4) and blocks Wnt1 signaling. Conclusion:The sclerostin/LRP6 interaction shares features with the well characterized nidogen/laminin interaction. Significance: NXI motifs are important in mediating interactions with ␤-propeller containing proteins.

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Section: Asn-93 Of Sclerostin Plays Key Role In Its Ability To Interamentioning

confidence: 53%

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

Holdsworth

Slocombe

Doyle

et al. 2012

Journal of Biological Chemistry

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“…Structural analysis of the LRP5 protein revealed that all amino acids involved in any of the HBM are clustered at an open binding pocket near the surface of the first b-propeller of LRP5 (119). The mutations do not have any effect on the functioning of the protein but rather disrupt the ligand binding of the extracellular inhibitors DKK1 and sclerostin (120,121,122), in which a short binding motif was found by structure analysis (123). The latter protein was identified by positional cloning for two other sclerosing bone disorders, Van Buchem disease and sclerosteosis (124,125,126,127).…”

Section: Identification Of the Role Of The Lrp5 Gene In Bonementioning

confidence: 97%

Genetics in Endocrinology: Autosomal dominant osteopetrosis revisited: lessons from recent studies

Bollerslev

Henriksen

Nielsen

et al. 2013

European Journal of Endocrinology

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Systematic studies of autosomal dominant osteopetrosis (ADO) were followed by the identification of underlying mutations giving unique possibilities to perform translational studies. What was previously designated ADO1 turned out to be a high bone mass phenotype caused by a missense mutation in the first propeller of LRP5, a region of importance for binding inhibitory proteins. Thereby, ADO1 cannot be regarded as a classical form of osteopetrosis but must now be considered a disease of LRP5 activation. ADO (Albers-Schönberg disease, or previously ADO2) is characterized by increased number of osteoclasts and a defect in the chloride transport system (ClC-7) of importance for acidification of the resorption lacuna (a form of Chloride Channel 7 Deficiency Osteopetrosis). Ex vivo studies of osteoclasts from ADO have shown that cells do form normally but have reduced resorption capacity and an expanded life span. Bone formation seems normal despite decreased osteoclast function. Uncoupling of formation from resorption makes ADO of interest for new strategies for treatment of osteoporosis. Recent studies have integrated bone metabolism in whole-body energy homeostasis. Patients with ADO may have decreased insulin levels indicating importance beyond bone metabolism. There seems to be a paradigm shift in the treatment of osteoporosis. Targeting ClC-7 might introduce a new principle of dual action. Drugs affecting ClC-7 could be antiresorptive, still allowing ongoing bone formation. Inversely, drugs affecting the inhibitory site of LRP5 might stimulate bone formation and inhibit resorption. Thereby, these studies have highlighted several intriguing treatment possibilities, employing novel modes of action, which could provide benefits to the treatment of osteoporosis.

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“…The remaining Wnts have not been tested in these assays. The top surfaces of P1 and P3 (and P2 and P4 as well) do not harbor N-glycosylation sites (Ahn et al 2011;Bourhis et al 2011;Chen et al 2011;Cheng et al 2011) and are likely the Wnt-binding interface. Indeed, missense substitutions of multiple top surface residues of P3 of LRP6, designed based on the crystal structure, diminish or enhance Wnt3a binding and signaling ( Fig.…”

Section: Two or More Wnt-binding Surfaces Of Lrp6mentioning

confidence: 99%

Frizzled and LRP5/6 Receptors for Wnt/ -Catenin Signaling

MacDonald

2012

Cold Spring Harbor Perspectives in Biology

531

411

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Frizzled and LRP5/6 are Wnt receptors that upon activation lead to stabilization of cytoplasmic b-catenin. In this study, we review the current knowledge of these two families of receptors, including their structures and interactions with Wnt proteins, and signaling mechanisms from receptor activation to the engagement of intracellular partners Dishevelled and Axin, and finally to the inhibition of b-catenin phosphorylation and ensuing b-catenin stabilization.T he Wnt/b-catenin pathway, or canonical Wnt pathway as it is often referred to, is an ancient and conserved signaling cascade involving b-catenin acting as a transcriptional coactivator (Logan and Nusse 2004). The pathway is best understood when considered in a two-state model of OFF (without Wnt) and ON (with Wnt). In the OFF state, cytoplasmic b-catenin is constitutively targeted for degradation by two multidomain scaffolding proteins, Axin and Adenomatous polyposis coli (APC), which facilitate the amino-terminal phosphorylation of b-catenin via the kinases GSK3 and CKIa. Phosphorylated b-catenin is recognized by the E3 ubiquitin ligase b-Trcp and is thus ubiquitinated and degraded by the proteasome, thereby maintaining low levels of free b-catenin in the cytoplasm and nucleus (MacDonald et al. 2009). In the ON state, a Wnt ligand binds to the seven-pass transmembrane receptor Frizzled (FZD) and the single-pass low-density lipoprotein receptor-related protein 5 or 6 (LRP5/6) ). The Wnt-FZD -LRP5/6 trimeric complex recruits Dishevelled (DVL) and Axin through the intracellular domains of FZD and LRP5/6, resulting in inhibition of b-catenin phosphorylation and thus ensuing b-catenin stabilization. The rise of cytoplasmic and nuclear levels of b-catenin levels promotes b-catenin partnering with the TCF/ LEF transcription factors for activation of Wntresponsive gene expression.Wnt/b-catenin signaling controls cell proliferation and differentiation and is a key regulatory mechanism for stem cells. As such, mutations in the Wnt pathway cause many diseases including cancer (Clevers 2006). All of the above "core" Wnt/b-catenin signaling components are present in vertebrates and the well-studied fruit fly Drosophila and are also encoded in sequenced genomes of radial symmetric Cnidarians Hydra magnipapillata and Nematostella vectensis (Guder et al. 2006) and of the primitive metazoan sponge Amphimedon queenslandica

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Wnt Antagonists Bind through a Short Peptide to the First β-Propeller Domain of LRP5/6

Cited by 151 publications

References 59 publications

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

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

Genetics in Endocrinology: Autosomal dominant osteopetrosis revisited: lessons from recent studies

Frizzled and LRP5/6 Receptors for Wnt/ -Catenin Signaling

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