title: Wnt antagonists bind through a short peptide to the first β-propeller domain of LRP5/6.
abstract: The Wnt pathway inhibitors DKK1 and sclerostin (SOST) are important therapeutic targets in diseases involving bone loss or damage. It has been appreciated that Wnt coreceptors LRP5/6 are also important, as human missense mutations that result in bone overgrowth (bone mineral density, or BMD, mutations) cluster to the E1 propeller domain of LRP5. Here, we report a crystal structure of LRP6 E1 bound to an antibody, revealing that the E1 domain is a peptide recognition module. Remarkably, the consensus E1 binding sequence is a close match to a conserved tripeptide motif present in all Wnt inhibitors that bind LRP5/6. We show that this motif is important for DKK1 and SOST binding to LRP6 and for inhibitory function, providing a detailed structural explanation for the effect of the BMD mutations.
authors.affiliation: Department of Early Discovery Biochemistry, Genentech Research and Early Development, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Bourhis
authors.forename: Weiru
authors.initials: W
authors.lastname: Wang
authors.forename: Christine
authors.initials: C
authors.lastname: Tam
authors.forename: Jiyoung
authors.initials: J
authors.lastname: Hwang
authors.forename: Yingnan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Didier
authors.initials: D
authors.lastname: Spittler
authors.forename: Oscar W
authors.initials: OW
authors.lastname: Huang
authors.forename: Yan
authors.initials: Y
authors.lastname: Gong
authors.forename: Alberto
authors.initials: A
authors.lastname: Estevez
authors.forename: Inna
authors.initials: I
authors.lastname: Zilberleyb
authors.forename: Lionel
authors.initials: L
authors.lastname: Rouge
authors.forename: Cecilia
authors.initials: C
authors.lastname: Chiu
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.forename: Mike
authors.initials: M
authors.lastname: Costa
authors.forename: Rami N
authors.initials: RN
authors.lastname: Hannoush
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Franke
authors.forename: Andrea G
authors.initials: AG
authors.lastname: Cochran
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies / Q000378:metabolism; D015519:Bone Density; D019485:Bone Morphogenetic Proteins / Q000737:chemistry / Q000378:metabolism*; D002846:Chromatography, Affinity; D002850:Chromatography, Gel; D016384:Consensus Sequence; D005819:Genetic Markers; D057809:HEK293 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism*; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000737:chemistry* / Q000378:metabolism; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000737:chemistry* / Q000378:metabolism; D020125:Mutation, Missense; D019151:Peptide Library; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D013329:Structure-Activity Relationship; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051155:Wnt1 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies; D019485:Bone Morphogenetic Proteins; C501126:DKK1 protein, human; D005819:Genetic Markers; D036341:Intercellular Signaling Peptides and Proteins; C555482:LRP5 protein, human; C555475:LRP6 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D019151:Peptide Library; C422903:SOST protein, human; C495247:WNT1 protein, human; C449090:WNT9B protein, human; D051153:Wnt Proteins; D051155:Wnt1 Protein