Structural and functional dissection of the DH and PH domains of oncogenic Bcr-Abl tyrosine kinase.
Structural and functional dissection of the DH and PH domains of oncogenic Bcr-Abl tyrosine kinase.
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DOI：
10.1038/s41467-017-02313-6
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发表时间：
2017-12-13
影响因子：
16.6
通讯作者：
Hantschel O
中科院分区：
文献类型：
--
作者：
Reckel S;Gehin C;Tardivon D;Georgeon S;Kükenshöner T;Löhr F;Koide A;Buchner L;Panjkovich A;Reynaud A;Pinho S;Gerig B;Svergun D;Pojer F;Güntert P;Dötsch V;Koide S;Gavin AC;Hantschel O
The two isoforms of the Bcr-Abl tyrosine kinase, p210 and p190, are associated with different leukemias and have a dramatically different signaling network, despite similar kinase activity. To provide a molecular rationale for these observations, we study the Dbl-homology (DH) and Pleckstrin-homology (PH) domains of Bcr-Abl p210, which constitute the only structural differences to p190. Here we report high-resolution structures of the DH and PH domains and characterize conformations of the DH–PH unit in solution. Our structural and functional analyses show no evidence that the DH domain acts as a guanine nucleotide exchange factor, whereas the PH domain binds to various phosphatidylinositol-phosphates. PH-domain mutants alter subcellular localization and result in decreased interactions with p210-selective interaction partners. Hence, the PH domain, but not the DH domain, plays an important role in the formation of the differential p210 and p190 Bcr-Abl signaling networks. The Bcr-Abl tyrosine kinases p210 and p190 are linked to different leukemias and differ by the Dbl homology (DH) and Pleckstrin-homology (PH) domains. Here the authors characterize structures of the Bcr-Abl p210 DH and PH domains and find that the PH domain is important for the cellular localization and signaling network of p210.
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影响因子：
3
作者：
Kirchner DK;Güntert P
通讯作者：
Güntert P
影响因子：
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Koide, Akiko;Wojcik, John;Gilbreth, Ryan N.;Hoey, Robert J.;Koide, Shohei
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Manor, Danny
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通讯作者：
Kim, Dong-Wook
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作者：
Jaiswal, Mamta;Dvorsky, Radovan;Ahmadian, Mohammad Reza
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