Structure and function of Norrin in assembly and activation of a Frizzled 4-Lrp5/6 complex

Jiyuan Ke, Kaleeckal G. Harikumar, Clara Erice, Chen Chen, Xin Gu, Liren Wang, Naomi Parker, Zhihong Cheng, Wenqing Xu, Bart O. Williams, Karsten Melcher, Laurence J. Miller, H. Eric Xu

Research output: Contribution to journalArticle

47 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2305-2319
Number of pages15
JournalGenes and Development
Volume27
Issue number21
DOIs
StatePublished - Nov 1 2013

Keywords

  • Cystine knot growth factor
  • Frizzled 4
  • Low-density lipoprotein receptor-related protein 5/6
  • Norrin structure
  • Tetraspanin 12
  • Wnt/β-catenin signaling

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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  • Cite this

    Ke, J., Harikumar, K. G., Erice, C., Chen, C., Gu, X., Wang, L., Parker, N., Cheng, Z., Xu, W., Williams, B. O., Melcher, K., Miller, L. J., & Eric Xu, H. (2013). Structure and function of Norrin in assembly and activation of a Frizzled 4-Lrp5/6 complex. Genes and Development, 27(21), 2305-2319. https://doi.org/10.1101/gad.228544.113