Wnt antagonists bind through a short peptide to the first β-propeller domain of LRP5/6

Eric Bourhis; Weiru Wang; Christine Tam; Jiyoung Hwang; Yingnan Zhang; Didier Spittler; Oscar W Huang; Yan Gong; Alberto Estevez; Inna Zilberleyb; Lionel Rouge; Cecilia Chiu; Yan Wu; Mike Costa; Rami N Hannoush; Yvonne Franke; Andrea G Cochran

doi:10.1016/j.str.2011.07.005

Wnt antagonists bind through a short peptide to the first β-propeller domain of LRP5/6

Structure. 2011 Oct 12;19(10):1433-42. doi: 10.1016/j.str.2011.07.005. Epub 2011 Sep 22.

Authors

Eric Bourhis¹, Weiru Wang, Christine Tam, Jiyoung Hwang, Yingnan Zhang, Didier Spittler, Oscar W Huang, Yan Gong, Alberto Estevez, Inna Zilberleyb, Lionel Rouge, Cecilia Chiu, Yan Wu, Mike Costa, Rami N Hannoush, Yvonne Franke, Andrea G Cochran

Affiliation

¹ Department of Early Discovery Biochemistry, Genentech Research and Early Development, 1 DNA Way, South San Francisco, CA 94080, USA.

PMID: 21944579
DOI: 10.1016/j.str.2011.07.005

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.

MeSH terms

Adaptor Proteins, Signal Transducing
Antibodies / metabolism
Bone Density
Bone Morphogenetic Proteins / chemistry
Bone Morphogenetic Proteins / metabolism*
Chromatography, Affinity
Chromatography, Gel
Consensus Sequence
Genetic Markers
HEK293 Cells
Humans
Intercellular Signaling Peptides and Proteins / chemistry
Intercellular Signaling Peptides and Proteins / metabolism*
Low Density Lipoprotein Receptor-Related Protein-5 / chemistry*
Low Density Lipoprotein Receptor-Related Protein-5 / metabolism
Low Density Lipoprotein Receptor-Related Protein-6 / chemistry*
Low Density Lipoprotein Receptor-Related Protein-6 / metabolism
Mutation, Missense
Peptide Library
Protein Binding
Protein Conformation
Protein Interaction Domains and Motifs*
Protein Interaction Mapping
Structure-Activity Relationship
Wnt Proteins / antagonists & inhibitors
Wnt Proteins / metabolism
Wnt Signaling Pathway
Wnt1 Protein / antagonists & inhibitors
Wnt1 Protein / metabolism

Substances

Adaptor Proteins, Signal Transducing
Antibodies
Bone Morphogenetic Proteins
DKK1 protein, human
Genetic Markers
Intercellular Signaling Peptides and Proteins
LRP5 protein, human
LRP6 protein, human
Low Density Lipoprotein Receptor-Related Protein-5
Low Density Lipoprotein Receptor-Related Protein-6
Peptide Library
SOST protein, human
WNT1 protein, human
WNT9B protein, human
Wnt Proteins
Wnt1 Protein

Associated data

PDB/3SOB
PDB/3SOQ
PDB/3SOV