title: Structure and function of Norrin in assembly and activation of a Frizzled 4-Lrp5/6 complex.
abstract: Norrin is a cysteine-rich growth factor that is required for angiogenesis in the eye, ear, brain, and female reproductive organs. It functions as an atypical Wnt ligand by specifically binding to the Frizzled 4 (Fz4) receptor. Here we report the crystal structure of Norrin, which reveals a unique dimeric structure with each monomer adopting a conserved cystine knot fold. Functional studies demonstrate that the novel Norrin dimer interface is required for Fz4 activation. Furthermore, we demonstrate that Norrin contains separate binding sites for Fz4 and for the Wnt ligand coreceptor Lrp5 (low-density lipoprotein-related protein 5) or Lrp6. Instead of inducing Fz4 dimerization, Norrin induces the formation of a ternary complex with Fz4 and Lrp5/6 by binding to their respective extracellular domains. These results provide crucial insights into the assembly and activation of the Norrin-Fz4-Lrp5/6 signaling complex.
authors.affiliation: Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA;
authors.forename: Jiyuan
authors.initials: J
authors.lastname: Ke
authors.forename: Kaleeckal G
authors.initials: KG
authors.lastname: Harikumar
authors.forename: Clara
authors.initials: C
authors.lastname: Erice
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.forename: Xin
authors.initials: X
authors.lastname: Gu
authors.forename: Liren
authors.initials: L
authors.lastname: Wang
authors.forename: Naomi
authors.initials: N
authors.lastname: Parker
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Cheng
authors.forename: Wenqing
authors.initials: W
authors.lastname: Xu
authors.forename: Bart O
authors.initials: BO
authors.lastname: Williams
authors.forename: Karsten
authors.initials: K
authors.lastname: Melcher
authors.forename: Laurence J
authors.initials: LJ
authors.lastname: Miller
authors.forename: H Eric
authors.initials: HE
authors.lastname: Xu
mesh_terms: D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D018360:Crystallography, X-Ray; D019281:Dimerization; D005136:Eye Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051157:Frizzled Receptors / Q000737:chemistry / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000737:chemistry / Q000378:metabolism*; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000737:chemistry / Q000378:metabolism*; D058619:Maltose-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D059470:Tetraspanins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000737:chemistry; D051176:beta Catenin / Q000378:metabolism
chemical_list: D005136:Eye Proteins; C402930:FZD4 protein, human; D051157:Frizzled Receptors; C555482:LRP5 protein, human; C555475:LRP6 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D058619:Maltose-Binding Proteins; C081848:NDP protein, human; D009419:Nerve Tissue Proteins; C545100:TSPAN12 protein, human; D059470:Tetraspanins; D016212:Transforming Growth Factor beta; D051176:beta Catenin
keywords: Frizzled 4; Norrin structure; Wnt/β-catenin signaling; cystine knot growth factor; low-density lipoprotein receptor-related protein 5/6; tetraspanin 12