Selective and Potent Peptide Binders of RNF43 for Wnt Signaling Inhibition

IF 10.4 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY
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*, 
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引用次数: 0

Abstract

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.

选择性和有效的RNF43肽结合物抑制Wnt信号
Wnt/β-catenin通路在人类肿瘤进展中起关键作用。细胞表面跨膜E3泛素连接酶环指43通过Wnt辅受体frizzed泛素化负调控Wnt信号。通过RNF43失活突变导致的异常Wnt信号传导已在多种形式的癌症中被发现,这突出了其在肿瘤生物学中的重要性。然而,RNF43功能的确切机制仍然难以捉摸,这主要是由于缺乏选择性的分子工具来检测或操纵内源性RNF43。在这里,我们提出了一系列二硫约束肽,包括gurr -1.6.12.2,它们对RNF43具有高亲和力和特异性。gurr -1.6.12.2可以作为一个有价值的研究工具来描述RNF43在各种情况下的活动。我们展示了其在免疫荧光中的应用,其中使用生物素化的gurr -1.6.12.2检测肠隐窝中的RNF43。然后,我们将实验和计算结构方法相结合,提出了gurr -1.6.12.2及其与RNF43结合的模型。重要的是,我们通过生产六价GUR-1.6.12.2分子生成了功能性RNF43- dcp,该分子通过与RNF43配体R-spondin(一种增强信号传导的RNF43配体)竞争,在细胞中表现出对Wnt信号传导的抑制活性。本文提出的RNF43结合物为研究和开发靶向Wnt信号的抗癌疗法提供了新的机会。在这里,我们报告选择性和有效的二硫约束RNF43肽结合物的发展。功能性六价肽通过与R-spondin竞争抑制细胞中的Wnt信号传导。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
ACS Central Science
ACS Central Science Chemical Engineering-General Chemical Engineering
CiteScore
25.50
自引率
0.50%
发文量
194
审稿时长
10 weeks
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.
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