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Structure and functional properties of Norrin mimic Wnt for signalling with Frizzled4, Lrp5/6, and proteoglycan.

Chang TH, Hsieh FL, Zebisch M, Harlos K, Elegheert J, Jones EY
Elife 4 (2015)
Related entries: 5bpb, 5bpu, 5bq8, 5bqb, 5bqc, 5bqe

Cited: 56 times
EuropePMC logo PMID: 26158506

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.

Reviews - 5bpq mentioned but not cited (1)

  1. Assembly and architecture of the Wnt/β-catenin signalosome at the membrane. DeBruine ZJ, Xu HE, Melcher K. Br J Pharmacol 174 4564-4574 (2017)

Articles - 5bpq mentioned but not cited (3)

  1. Structure and functional properties of Norrin mimic Wnt for signalling with Frizzled4, Lrp5/6, and proteoglycan. Chang TH, Hsieh FL, Zebisch M, Harlos K, Elegheert J, Jones EY. Elife 4 (2015)
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Reviews citing this publication (18)

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Articles citing this publication (34)

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  2. Reck and Gpr124 Are Essential Receptor Cofactors for Wnt7a/Wnt7b-Specific Signaling in Mammalian CNS Angiogenesis and Blood-Brain Barrier Regulation. Cho C, Smallwood PM, Nathans J. Neuron 95 1056-1073.e5 (2017)
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  4. TSPAN12 Is a Norrin Co-receptor that Amplifies Frizzled4 Ligand Selectivity and Signaling. Lai MB, Zhang C, Shi J, Johnson V, Khandan L, McVey J, Klymkowsky MW, Chen Z, Junge HJ. Cell Rep 19 2809-2822 (2017)
  5. Structure of human Frizzled5 by fiducial-assisted cryo-EM supports a heterodimeric mechanism of canonical Wnt signaling. Tsutsumi N, Mukherjee S, Waghray D, Janda CY, Jude KM, Miao Y, Burg JS, Aduri NG, Kossiakoff AA, Gati C, Garcia KC. Elife 9 e58464 (2020)
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  7. A synthetic anti-Frizzled antibody engineered for broadened specificity exhibits enhanced anti-tumor properties. Pavlovic Z, Adams JJ, Blazer LL, Gakhal AK, Jarvik N, Steinhart Z, Robitaille M, Mascall K, Pan J, Angers S, Moffat J, Sidhu SS. MAbs 10 1157-1167 (2018)
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  14. Variations in Proteins Dielectric Constants. Amin M, Küpper J. ChemistryOpen 9 691-694 (2020)
  15. Molecular rationale for antibody-mediated targeting of the hantavirus fusion glycoprotein. Rissanen I, Stass R, Krumm SA, Seow J, Hulswit RJ, Paesen GC, Hepojoki J, Vapalahti O, Lundkvist Å, Reynard O, Volchkov V, Doores KJ, Huiskonen JT, Bowden TA. Elife 9 e58242 (2020)
  16. The C-terminal dimerization domain of the respiratory mucin MUC5B functions in mucin stability and intracellular packaging before secretion. Ridley C, Lockhart-Cairns MP, Collins RF, Jowitt TA, Subramani DB, Kesimer M, Baldock C, Thornton DJ. J Biol Chem 294 17105-17116 (2019)
  17. Intrinsic disorder in spondins and some of their interacting partners. Alowolodu O, Johnson G, Alashwal L, Addou I, Zhdanova IV, Uversky VN. Intrinsically Disord Proteins 4 e1255295 (2016)
  18. Antiepileptic Drug Carbamazepine Binds to a Novel Pocket on the Wnt Receptor Frizzled-8. Zhao Y, Ren J, Hillier J, Lu W, Jones EY. J Med Chem 63 3252-3260 (2020)
  19. Structure of the RECK CC domain, an evolutionary anomaly. Chang TH, Hsieh FL, Smallwood PM, Gabelli SB, Nathans J. Proc Natl Acad Sci U S A 117 15104-15111 (2020)
  20. Biological Effects of Phosphocitrate on Osteoarthritic Articular Chondrocytes. Sun Y, Franklin AM, Mauerhan DR, Hanley EN. Open Rheumatol J 11 62-74 (2017)
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  26. Structure of the Wnt-Frizzled-LRP6 initiation complex reveals the basis for coreceptor discrimination. Tsutsumi N, Hwang S, Waghray D, Hansen S, Jude KM, Wang N, Miao Y, Glassman CR, Caveney NA, Janda CY, Hannoush RN, Garcia KC. Proc Natl Acad Sci U S A 120 e2218238120 (2023)
  27. Substrate Specificity and Structural Modeling of Human Carboxypeptidase Z: A Unique Protease with a Frizzled-Like Domain. Garcia-Pardo J, Tanco S, Garcia-Guerrero MC, Dasgupta S, Avilés FX, Lorenzo J, Fricker LD. Int J Mol Sci 21 E8687 (2020)
  28. Systemic gene therapy rescues retinal dysfunction and hearing loss in a model of Norrie disease. Pauzuolyte V, Patel A, Wawrzynski JR, Ingham NJ, Leong YC, Karda R, Bitner-Glindzicz M, Berger W, Waddington SN, Steel KP, Sowden JC. EMBO Mol Med 15 e17393 (2023)
  29. Therapeutic blood-brain barrier modulation and stroke treatment by a bioengineered FZD4-selective WNT surrogate in mice. Ding J, Lee SJ, Vlahos L, Yuki K, Rada CC, van Unen V, Vuppalapaty M, Chen H, Sura A, McCormick AK, Tomaske M, Alwahabi S, Nguyen H, Nowatzke W, Kim L, Kelly L, Vollrath D, Califano A, Yeh WC, Li Y, Kuo CJ. Nat Commun 14 2947 (2023)
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  32. Structural insights into plasmalemma vesicle-associated protein (PLVAP): Implications for vascular endothelial diaphragms and fenestrae. Chang TH, Hsieh FL, Gu X, Smallwood PM, Kavran JM, Gabelli SB, Nathans J. Proc Natl Acad Sci U S A 120 e2221103120 (2023)
  33. Structure of WNT inhibitor adenomatosis polyposis coli down-regulated 1 (APCDD1), a cell-surface lipid-binding protein. Hsieh FL, Chang TH, Gabelli SB, Nathans J. Proc Natl Acad Sci U S A 120 e2217096120 (2023)
  34. Wnt Receptor Frizzled-4 as a Marker for Isolation of Enteric Neural Progenitors in Human Children. Neckel PH, Scharr M, Seid K, Nothelfer K, Fuchs J, Obermayr F, Hirt B, Huber SM, Just L. Cells 8 E792 (2019)


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