5BPU

Crystal structure of Norrin, a Wnt signalling activator, Crystal Form I

Summary for 5BPU

• Entry DOI: 10.2210/pdb5bpu/pdb
• Related: 4MY2
• Descriptor: Norrin, (GGL)EEEEEE, (GGL)EEE, ... (4 entities in total)
• Functional Keywords: wnt signalling pathway, norrie disease protein, cystine-knot like growth factor, ligand for frizzled 4 receptor, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 8
• Total formula weight: 83144.52

Authors

Chang, T.-H.,Hsieh, F.-L.,Harlos, K.,Jones, E.Y. (deposition date: 2015-05-28, release date: 2015-07-01, Last modification date: 2019-07-10)

Primary citation

Chang, T.H.,Hsieh, F.L.,Zebisch, M.,Harlos, K.,Elegheert, J.,Jones, E.Y.
Structure and functional properties of Norrin mimic Wnt for signalling with Frizzled4, Lrp5/6, and proteoglycan.
Elife, 4:e06554-, 2015

PubMed Abstract: Wnt signalling regulates multiple processes including angiogenesis, inflammation, and tumorigenesis. Norrin (Norrie Disease Protein) is a cystine-knot like growth factor. Although unrelated to Wnt, Norrin activates the Wnt/β-catenin pathway. Signal complex formation involves Frizzled4 (Fz4), low-density lipoprotein receptor related protein 5/6 (Lrp5/6), Tetraspanin-12 and glycosaminoglycans (GAGs). Here, we report crystallographic and small-angle X-ray scattering analyses of Norrin in complex with Fz4 cysteine-rich domain (Fz4CRD), of this complex bound with GAG analogues, and of unliganded Norrin and Fz4CRD. Our structural, biophysical and cellular data, map Fz4 and putative Lrp5/6 binding sites to distinct patches on Norrin, and reveal a GAG binding site spanning Norrin and Fz4CRD. These results explain numerous disease-associated mutations. Comparison with the Xenopus Wnt8-mouse Fz8CRD complex reveals Norrin mimics Wnt for Frizzled recognition. The production and characterization of wild-type and mutant Norrins reported here open new avenues for the development of therapeutics to combat abnormal Norrin/Wnt signalling.

PubMed: 26158506
DOI: 10.7554/eLife.06554

Experimental method

X-RAY DIFFRACTION (2.4 Å)