Sunhee Hwang, , , Paula Flórez Salcedo, , , Antonion Korcari, , , John M. Nicoludis, , , Estefania Martinez Valdivia, , , Lingling Peng, , , Aaron T. Balana, , , Justin Mak, , , Christopher M. Crittenden, , , Amin Famili, , , Peter Liu, , , David Castillo-Azofeifa, , , Rami N. Hannoush, , , Stephen E. Miller, , , Christina I. Schroeder, , and , Xinxin Gao*,
{"title":"选择性和有效的RNF43肽结合物抑制Wnt信号","authors":"Sunhee Hwang, , , Paula Flórez Salcedo, , , Antonion Korcari, , , John M. Nicoludis, , , Estefania Martinez Valdivia, , , Lingling Peng, , , Aaron T. Balana, , , Justin Mak, , , Christopher M. Crittenden, , , Amin Famili, , , Peter Liu, , , David Castillo-Azofeifa, , , Rami N. Hannoush, , , Stephen E. Miller, , , Christina I. Schroeder, , and , Xinxin Gao*, ","doi":"10.1021/acscentsci.5c00744","DOIUrl":null,"url":null,"abstract":"<p >The Wnt/β-catenin pathway is critical in human tumor progression. Cell-surface transmembrane E3 ubiquitin ligase ring finger 43 negatively regulates Wnt signaling through ubiquitination of Wnt coreceptor Frizzled. Aberrant Wnt signaling through inactivating mutations of RNF43 has been identified in various forms of cancers, highlighting its significance in tumor biology. However, the precise mechanism underlying the function of RNF43 remains elusive, largely due to the absence of selective molecular tools allowing for detection or manipulation of endogenous RNF43. Here we present a series of disulfide-constrained peptides, including GUR-1.6.12.2, which exhibit high affinity and specificity against RNF43. GUR-1.6.12.2 can be used as a valuable research tool to delineate RNF43 activity in various contexts. We showcased its application in immunofluorescence, where RNF43 was detected in intestinal crypts using biotinylated GUR-1.6.12.2. We then combined experimental and computational structural approaches to propose a model of GUR-1.6.12.2 and its binding to RNF43. Importantly, we generated a functional RNF43-DCP by producing a hexavalent GUR-1.6.12.2 molecule, which exhibited inhibitory activity against Wnt signaling in cells by competing with R-spondin, a RNF43 ligand that potentiates signaling. The RNF43 binders presented here offer new opportunities for the research and development of anticancer therapies targeting Wnt signaling with improved selectivity.</p><p >Here we report the development of selective and potent disulfide-constrained peptide binders of RNF43. The functional hexavalent peptide inhibits Wnt signaling in cells by competing with R-spondin.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 9","pages":"1670–1681"},"PeriodicalIF":10.4000,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acscentsci.5c00744","citationCount":"0","resultStr":"{\"title\":\"Selective and Potent Peptide Binders of RNF43 for Wnt Signaling Inhibition\",\"authors\":\"Sunhee Hwang, , , Paula Flórez Salcedo, , , Antonion Korcari, , , John M. Nicoludis, , , Estefania Martinez Valdivia, , , Lingling Peng, , , Aaron T. Balana, , , Justin Mak, , , Christopher M. Crittenden, , , Amin Famili, , , Peter Liu, , , David Castillo-Azofeifa, , , Rami N. Hannoush, , , Stephen E. Miller, , , Christina I. Schroeder, , and , Xinxin Gao*, \",\"doi\":\"10.1021/acscentsci.5c00744\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >The Wnt/β-catenin pathway is critical in human tumor progression. Cell-surface transmembrane E3 ubiquitin ligase ring finger 43 negatively regulates Wnt signaling through ubiquitination of Wnt coreceptor Frizzled. Aberrant Wnt signaling through inactivating mutations of RNF43 has been identified in various forms of cancers, highlighting its significance in tumor biology. However, the precise mechanism underlying the function of RNF43 remains elusive, largely due to the absence of selective molecular tools allowing for detection or manipulation of endogenous RNF43. Here we present a series of disulfide-constrained peptides, including GUR-1.6.12.2, which exhibit high affinity and specificity against RNF43. GUR-1.6.12.2 can be used as a valuable research tool to delineate RNF43 activity in various contexts. We showcased its application in immunofluorescence, where RNF43 was detected in intestinal crypts using biotinylated GUR-1.6.12.2. We then combined experimental and computational structural approaches to propose a model of GUR-1.6.12.2 and its binding to RNF43. Importantly, we generated a functional RNF43-DCP by producing a hexavalent GUR-1.6.12.2 molecule, which exhibited inhibitory activity against Wnt signaling in cells by competing with R-spondin, a RNF43 ligand that potentiates signaling. The RNF43 binders presented here offer new opportunities for the research and development of anticancer therapies targeting Wnt signaling with improved selectivity.</p><p >Here we report the development of selective and potent disulfide-constrained peptide binders of RNF43. 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Selective and Potent Peptide Binders of RNF43 for Wnt Signaling Inhibition
The Wnt/β-catenin pathway is critical in human tumor progression. Cell-surface transmembrane E3 ubiquitin ligase ring finger 43 negatively regulates Wnt signaling through ubiquitination of Wnt coreceptor Frizzled. Aberrant Wnt signaling through inactivating mutations of RNF43 has been identified in various forms of cancers, highlighting its significance in tumor biology. However, the precise mechanism underlying the function of RNF43 remains elusive, largely due to the absence of selective molecular tools allowing for detection or manipulation of endogenous RNF43. Here we present a series of disulfide-constrained peptides, including GUR-1.6.12.2, which exhibit high affinity and specificity against RNF43. GUR-1.6.12.2 can be used as a valuable research tool to delineate RNF43 activity in various contexts. We showcased its application in immunofluorescence, where RNF43 was detected in intestinal crypts using biotinylated GUR-1.6.12.2. We then combined experimental and computational structural approaches to propose a model of GUR-1.6.12.2 and its binding to RNF43. Importantly, we generated a functional RNF43-DCP by producing a hexavalent GUR-1.6.12.2 molecule, which exhibited inhibitory activity against Wnt signaling in cells by competing with R-spondin, a RNF43 ligand that potentiates signaling. The RNF43 binders presented here offer new opportunities for the research and development of anticancer therapies targeting Wnt signaling with improved selectivity.
Here we report the development of selective and potent disulfide-constrained peptide binders of RNF43. The functional hexavalent peptide inhibits Wnt signaling in cells by competing with R-spondin.
期刊介绍:
ACS Central Science publishes significant primary reports on research in chemistry and allied fields where chemical approaches are pivotal. As the first fully open-access journal by the American Chemical Society, it covers compelling and important contributions to the broad chemistry and scientific community. "Central science," a term popularized nearly 40 years ago, emphasizes chemistry's central role in connecting physical and life sciences, and fundamental sciences with applied disciplines like medicine and engineering. The journal focuses on exceptional quality articles, addressing advances in fundamental chemistry and interdisciplinary research.