Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A.
Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A.
复制标题
CIP2A 抑制 PP2A-B56α 和致癌性的结构机制。
DOI：
10.1038/s41467-023-36693-9
复制
发表时间：
2023-02-28
影响因子：
16.6
通讯作者：
Westermarck, Jukka
中科院分区：
文献类型：
--
作者：
Pavic, Karolina;Gupta, Nikhil;Omella, Judit Domenech;Derua, Rita;Aakula, Anna;Huhtaniemi, Riikka;Maatta, Juha A.;Hofflin, Nico;Okkeri, Juha;Wang, Zhizhi;Kauko, Otto;Varjus, Roosa;Honkanen, Henrik;Abankwa, Daniel;Kohn, Maja;Hytonen, Vesa P.;Xu, Wenqing;Nilsson, Jakob;Page, Rebecca;Janssens, Veerle;Leitner, Alexander;Westermarck, Jukka
蛋白磷酸酶2A（PP 2A）异源三聚体PP 2A-B56 α是一种人类肿瘤抑制因子。然而，在癌症中抑制PP 2A-B56 α的分子机制知之甚少。在这里，我们报告了癌蛋白CIP 2A抑制PP 2A-B56 α的分子水平细节和结构机制。在与PP 2A-B56 α三聚体直接结合后，CIP 2A置换PP 2A-A亚基，从而劫持B56α和催化性PP 2Ac亚基以形成CIP 2A-B56 α-PP 2Ac假三聚体。此外，CIP 2A通过阻断B56α上的LxxIxE基序底物结合口袋与B56α底物竞争结合。与CIP 2A在人类癌症中的致癌活性相关，N-末端头部结构域介导的与B56α的相互作用使CIP 2A蛋白稳定。在功能上，CRISPR/Cas9介导的头部结构域的单氨基酸突变减弱了MYC表达和MEK磷酸化，并消除了三阴性乳腺癌体内肿瘤生长。总的来说，我们发现了一种独特的多步劫持和沉默蛋白复合物调节机制，导致肿瘤抑制因子PP 2A-B56 α抑制。此外，这些结果揭示了CIP 2A致癌活性的结构决定因素，可能有助于CIP 2A在癌症和其他疾病中的治疗调节。肿瘤抑制因子在癌症中被抑制，它们的重新激活可以提供新的治疗机会。在这里，作者研究了乳腺癌细胞中人类肿瘤抑制蛋白磷酸酶2A被癌蛋白CIP 2A抑制的结构机制。
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. Tumour suppressors are inhibited in cancers and their reactivation could provide novel therapy opportunities. Here, the authors study the structural mechanism by which human tumour suppressor Protein Phosphatase 2A is inhibited in breast cancer cells by the oncoprotein CIP2A.
登录
查看更多内容
影响因子：
29
作者：
Hatting M;Rines AK;Luo C;Tabata M;Sharabi K;Hall JA;Verdeguer F;Trautwein C;Puigserver P
通讯作者：
Puigserver P
影响因子：
50.3
作者：
Chen, W;Possemato, R;Hahn, WC
通讯作者：
Hahn, WC
影响因子：
50.3
作者：
Elgendy, Mohamed;Ciro, Marco;Minucci, Saverio
通讯作者：
Minucci, Saverio
影响因子：
3.5
作者：
Choi, Yeon A.;Park, Jeong Su;Yang, Young
通讯作者：
Yang, Young
影响因子：
11.5
作者：
Come, Christophe;Laine, Anni;Westermarck, Jukka
通讯作者：
Westermarck, Jukka