Structural Basis of the Interaction between Human Axin2 and SIAH1 in the Wnt/beta-Catenin Signaling Pathway

doi:10.3390/biom13040647

	Structural Basis of the Interaction between Human Axin2 and SIAH1 in the Wnt/beta-Catenin Signaling Pathway
	Chen, Lianqi 1,2; Liu, Yan-Ping 1,2; Tian, Li-Fei 1; Li, Mingzhou 1,2; Yang, Shuyu 1,2; Wang, Song 1; Xu, Wenqing1,3 ; Yan, Xiao-Xue 1
	2023-04-01
发表期刊	BIOMOLECULES
EISSN	2218-273X
卷号	13 期号:4
发表状态	已发表
DOI	10.3390/biom13040647
摘要	The scaffolding protein Axin is an important regulator of the Wnt signaling pathway, and its dysfunction is closely related to carcinogenesis. Axin could affect the assembly and dissociation of the beta-catenin destruction complex. It can be regulated by phosphorylation, poly-ADP-ribosylation, and ubiquitination. The E3 ubiquitin ligase SIAH1 participates in the Wnt pathway by targeting various components for degradation. SIAH1 is also implicated in the regulation of Axin2 degradation, but the specific mechanism remains unclear. Here, we verified that the Axin2-GSK3 binding domain (GBD) was sufficient for SIAH1 binding by the GST pull-down assay. Our crystal structure of the Axin2/SIAH1 complex at 2.53 angstrom resolution reveals that one Axin2 molecule binds to one SIAH1 molecule via its GBD. These interactions critically depend on a highly conserved peptide (361)EMTPVEPA(368) within the Axin2-GBD, which forms a loop and binds to a deep groove formed by beta 1, beta 2, and beta 3 of SIAH1 by the N-terminal hydrophilic amino acids Arg361 and Thr363 and the C-terminal VxP motif. The novel binding mode indicates a promising drug-binding site for regulating Wnt/beta-catenin signaling.
关键词	Wnt signaling pathway Axis inhibition protein Axin2 E3 ubiquitin-protein ligase SIAH1 GSK3-binding site X-ray crystal structure
URL	查看原文
收录类别	SCI
语种	英语
资助项目	Chinese Academy of Sciences Pilot Strategic Science and Technology Projects B grant[XDB37030302] ; National Natural Science Foundation of China[32171218]
WOS研究方向	Biochemistry & Molecular Biology
WOS类目	Biochemistry & Molecular Biology
WOS记录号	WOS:000979372000001
出版者	MDPI
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/301096
专题	生命科学与技术学院生命科学与技术学院_PI研究组_许文青组
通讯作者	Xu, Wenqing; Yan, Xiao-Xue
作者单位	1.Chinese Acad Sci, CAS Ctr Excellence Biomacromol, Natl Lab Biomacromol, Inst Biophys, Beijing 100101, Peoples R China 2.Univ Chinese Acad Sci, Coll Life Sci, Beijing 100049, Peoples R China 3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
通讯作者单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Chen, Lianqi,Liu, Yan-Ping,Tian, Li-Fei,et al. Structural Basis of the Interaction between Human Axin2 and SIAH1 in the Wnt/beta-Catenin Signaling Pathway[J]. BIOMOLECULES,2023,13(4).
APA	Chen, Lianqi.,Liu, Yan-Ping.,Tian, Li-Fei.,Li, Mingzhou.,Yang, Shuyu.,...&Yan, Xiao-Xue.(2023).Structural Basis of the Interaction between Human Axin2 and SIAH1 in the Wnt/beta-Catenin Signaling Pathway.BIOMOLECULES,13(4).
MLA	Chen, Lianqi,et al."Structural Basis of the Interaction between Human Axin2 and SIAH1 in the Wnt/beta-Catenin Signaling Pathway".BIOMOLECULES 13.4(2023).