Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A

doi:10.1038/s41467-023-36693-9

	Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A
	Pavic, Karolina 1,2,3; Gupta, Nikhil 1,2; Omella, Judit Domenech 4; Derua, Rita 4,5; Aakula, Anna 1,2; Huhtaniemi, Riikka 1,2; Maatta, Juha A.6,7; Hofflin, Nico 8; Okkeri, Juha 1,2; Wang, Zhizhi9 ; Kauko, Otto 1,2; Varjus, Roosa 1,2; Honkanen, Henrik 1,2; Abankwa, Daniel 3; Kohn, Maja 8,10; Hytonen, Vesa P.6,7; Xu, Wenqing9 ; Nilsson, Jakob 11; Page, Rebecca 12; Janssens, Veerle 4; Leitner, Alexander 13; Westermarck, Jukka 1,2,14
	2023-12-01
发表期刊	NATURE COMMUNICATIONS;
ISSN	2041-1723
EISSN	2041-1723
卷号	14 期号:1
发表状态	已发表
DOI	10.1038/s41467-023-36693-9
摘要	The protein phosphatase 2A (PP2A) heterotrimer PP2A-B56α is a human tumour suppressor. However, the molecular mechanisms inhibiting PP2A-B56α in cancer are poorly understood. Here, we report molecular level details and structural mechanisms of PP2A-B56α inhibition by an oncoprotein CIP2A. Upon direct binding to PP2A-B56α trimer, CIP2A displaces the PP2A-A subunit and thereby hijacks both the B56α, and the catalytic PP2Ac subunit to form a CIP2A-B56α-PP2Ac pseudotrimer. Further, CIP2A competes with B56α substrate binding by blocking the LxxIxE-motif substrate binding pocket on B56α. Relevant to oncogenic activity of CIP2A across human cancers, the N-terminal head domain-mediated interaction with B56α stabilizes CIP2A protein. Functionally, CRISPR/Cas9-mediated single amino acid mutagenesis of the head domain blunted MYC expression and MEK phosphorylation, and abrogated triple-negative breast cancer in vivo tumour growth. Collectively, we discover a unique multi-step hijack and mute protein complex regulation mechanism resulting in tumour suppressor PP2A-B56α inhibition. Further, the results unfold a structural determinant for the oncogenic activity of CIP2A, potentially facilitating therapeutic modulation of CIP2A in cancer and other diseases.
学科门类	Chemistry (all) ; Biochemistry, Genetics and Molecular Biology (all) ; Multidisciplinary ; Physics and Astronomy (all)
URL	查看原文
收录类别	SCOPUS ; SCI
语种	英语
资助项目	Academy of Finland["331237","331946"] ; F.W.O. - Vlaanderen (Research Foundation - Flanders)["G0B0116N","G0B1719N","1S77521N"] ; Belgian Foundation against Cancer[R01GM144483] ; NIH NIGMS[C24/17/073] ; null[FA/2020/1330]
WOS研究方向	Science & Technology - Other Topics
WOS类目	Multidisciplinary Sciences
WOS记录号	WOS:000955827800018
出版者	NATURE PORTFOLIO
原始文献类型	Article
Scopus 记录号	2-s2.0-85149153582
来源库	SCOPUS
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/286494
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	Westermarck, Jukka
作者单位	1.Univ Turku, Turku Biosci Ctr, Turku 20520, Finland 2.Abo Akad Univ, Turku 20520, Finland 3.Univ Luxembourg, Dept Life Sci & Med, Canc Cell Biol & Drug Discovery Grp, Esch Sur Alzette, Luxembourg 4.Katholieke Univ Leuven, Dept Cellular & Mol Med, Lab Prot Phosphorylat & Prote, Univ Leuven, B-3000 Leuven, Belgium 5.Katholieke Univ Leuven, SyBioMa, Univ Leuven, B-3000 Leuven, Belgium 6.Tampere Univ, Fac Med & Hlth Technol, Tampere 33520, Finland 7.Fimlab Labs, Tampere 33520, Finland 8.Univ Freiburg, Inst Biol 3, Fac Biol, D-79104 Freiburg, Germany 9.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China 10.Univ Freiburg, Signalling Res Ctr BIOSS & CIBSS, Freiburg, Germany 11.Univ Copenhagen, Novo Nordisk Fdn Ctr Prot Res, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark 12.Univ Arizona, Dept Chem & Biochem, Tucson, AZ USA 13.Swiss Fed Inst Technol, Inst Mol Syst Biol, Dept Biol, CH-8093 Zurich, Switzerland 14.Univ Turku, Inst Biomed, Turku 20520, Finland
推荐引用方式 GB/T 7714	Pavic, Karolina,Gupta, Nikhil,Omella, Judit Domenech,et al. Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A[J]. NATURE COMMUNICATIONS;,2023,14(1).
APA	Pavic, Karolina.,Gupta, Nikhil.,Omella, Judit Domenech.,Derua, Rita.,Aakula, Anna.,...&Westermarck, Jukka.(2023).Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A.NATURE COMMUNICATIONS;,14(1).
MLA	Pavic, Karolina,et al."Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A".NATURE COMMUNICATIONS; 14.1(2023).