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Cell Research (2015) 25:1078-1081. 2015 IBCB, SIBS, CAS All rights reserved 1001-0602/15 $ 32.00 www.nature.com/cr
LETTER TO THE EDITOR
Structural basis of the Norrin-Frizzled 4 interaction
Cell Research (2015) 25:1078-1081. doi:10.1038/cr.2015.92; published online 31 July 2015
Dear Editor,
Norrin, also known as the Norrie disease protein or X-linked exudative vitreoretinopathy 2 protein, is a secreted retinal growth factor with angiogenic and neuroprotective properties. Mutations in the NPD gene, which encodes the Norrin protein, are associated with Norrie disease, familial exudative vitreoretinopathy (FEVR), retinopathy of prematurity (ROP), and other retinal hypovascularization diseases [1, 2]. Norrin has a weak homology with TGF-, but no signicant sequence homology with Wnt proteins. The crystal structure of Norrin revealed a dimeric complex of Norrin that folds more like TGF- than Wnt [3]. However, Norrin does not activate the TGF- pathway. Instead, despite its structure being distinct from that of Wnt proteins, Norrin functions predominantly through the activation of the canonical Wnt/-catenin signaling pathway. Frizzled 4 (Fz4), but not other Frizzled family members, serves as the primary receptor for Norrin on the cell surface. The Norrin-Fz4 interaction is essential for Norrin signaling and function, as both NPD mutations and FZD4 mutations are associated with FEVR. How Norrin activates the Wnt/-catenin signaling pathway through its interaction with Fz4 remains enigmatic.
The 133-residue Norrin forms a covalent homodimer, with three pairs of intermolecular disulfide bonds, in addition to four pairs of intramolecular disulde bonds in each Norrin subunit [3]. This structure does not immediately explain that Norrin can specically recognize Fz4, which is also a receptor for canonical Wnt proteins (e.g., Wnt8) [4], and activate the canonical Wnt/-catenin signaling pathway inside the cell. Frizzled proteins, along with smoothened, a hedgehog regulator, form the class F GPCR family. This family of receptors only weakly activates G-protein or arrestin pathways, the canonical signaling mechanisms downstream of the other GPCR classes. Like other Frizzled proteins, Fz4 contains a ~120-residue N-terminal extracellular cysteine-rich domain (CRD) followed by the 7-helix transmembrane domain. Due to the technical difculties generating soluble Norrin and Wnt proteins, the only complex structure available for the Frizzled family is that of the Wnt8/Fz8-
CRD complex [5]. Structural information regarding Norrin-Fz4 interaction would provide key insights into many important aspects of cell signaling.
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