Structures of Wnt-antagonist ZNRF3 and its complex with R-spondin 1 and implications for signaling.

Zinc RING finger 3 (ZNRF3) and its homolog RING finger 43 (RNF43) antagonize Wnt signaling in adult stem cells by ubiquitinating Frizzled receptors (FZD), which leads to endocytosis of the Wnt receptor. Conversely, binding of ZNRF3/RNF43 to LGR4-6 - R-spondin blocks Frizzled ubiquitination and enhan...

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Autores principales:	Weng Chuan Peng, Wim de Lau, Pramod K Madoori, Federico Forneris, Joke C M Granneman, Hans Clevers, Piet Gros
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ffe8805d8728401daf6954e4ef9835cb
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spelling	oai:doaj.org-article:ffe8805d8728401daf6954e4ef9835cb2021-11-18T08:42:10ZStructures of Wnt-antagonist ZNRF3 and its complex with R-spondin 1 and implications for signaling.1932-620310.1371/journal.pone.0083110https://doaj.org/article/ffe8805d8728401daf6954e4ef9835cb2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24349440/?tool=EBIhttps://doaj.org/toc/1932-6203Zinc RING finger 3 (ZNRF3) and its homolog RING finger 43 (RNF43) antagonize Wnt signaling in adult stem cells by ubiquitinating Frizzled receptors (FZD), which leads to endocytosis of the Wnt receptor. Conversely, binding of ZNRF3/RNF43 to LGR4-6 - R-spondin blocks Frizzled ubiquitination and enhances Wnt signaling. Here, we present crystal structures of the ZNRF3 ectodomain and its complex with R-spondin 1 (RSPO1). ZNRF3 binds RSPO1 and LGR5-RSPO1 with micromolar affinity via RSPO1 furin-like 1 (Fu1) domain. Anonychia-related mutations in RSPO4 support the importance of the observed interface. The ZNRF3-RSPO1 structure resembles that of LGR5-RSPO1-RNF43, though Fu2 of RSPO1 is variably oriented. The ZNRF3-binding site overlaps with trans-interactions observed in 2:2 LGR5-RSPO1 complexes, thus binding of ZNRF3/RNF43 would disrupt such an arrangement. Sequence conservation suggests a single ligand-binding site on ZNRF3, consistent with the proposed competing binding role of ZNRF3/RNF43 in Wnt signaling.Weng Chuan PengWim de LauPramod K MadooriFederico FornerisJoke C M GrannemanHans CleversPiet GrosPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 12, p e83110 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Weng Chuan Peng Wim de Lau Pramod K Madoori Federico Forneris Joke C M Granneman Hans Clevers Piet Gros Structures of Wnt-antagonist ZNRF3 and its complex with R-spondin 1 and implications for signaling.
description	Zinc RING finger 3 (ZNRF3) and its homolog RING finger 43 (RNF43) antagonize Wnt signaling in adult stem cells by ubiquitinating Frizzled receptors (FZD), which leads to endocytosis of the Wnt receptor. Conversely, binding of ZNRF3/RNF43 to LGR4-6 - R-spondin blocks Frizzled ubiquitination and enhances Wnt signaling. Here, we present crystal structures of the ZNRF3 ectodomain and its complex with R-spondin 1 (RSPO1). ZNRF3 binds RSPO1 and LGR5-RSPO1 with micromolar affinity via RSPO1 furin-like 1 (Fu1) domain. Anonychia-related mutations in RSPO4 support the importance of the observed interface. The ZNRF3-RSPO1 structure resembles that of LGR5-RSPO1-RNF43, though Fu2 of RSPO1 is variably oriented. The ZNRF3-binding site overlaps with trans-interactions observed in 2:2 LGR5-RSPO1 complexes, thus binding of ZNRF3/RNF43 would disrupt such an arrangement. Sequence conservation suggests a single ligand-binding site on ZNRF3, consistent with the proposed competing binding role of ZNRF3/RNF43 in Wnt signaling.
format	article
author	Weng Chuan Peng Wim de Lau Pramod K Madoori Federico Forneris Joke C M Granneman Hans Clevers Piet Gros
author_facet	Weng Chuan Peng Wim de Lau Pramod K Madoori Federico Forneris Joke C M Granneman Hans Clevers Piet Gros
author_sort	Weng Chuan Peng
title	Structures of Wnt-antagonist ZNRF3 and its complex with R-spondin 1 and implications for signaling.
title_short	Structures of Wnt-antagonist ZNRF3 and its complex with R-spondin 1 and implications for signaling.
title_full	Structures of Wnt-antagonist ZNRF3 and its complex with R-spondin 1 and implications for signaling.
title_fullStr	Structures of Wnt-antagonist ZNRF3 and its complex with R-spondin 1 and implications for signaling.
title_full_unstemmed	Structures of Wnt-antagonist ZNRF3 and its complex with R-spondin 1 and implications for signaling.
title_sort	structures of wnt-antagonist znrf3 and its complex with r-spondin 1 and implications for signaling.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/ffe8805d8728401daf6954e4ef9835cb
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Structures of Wnt-antagonist ZNRF3 and its complex with R-spondin 1 and implications for signaling.

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