Reckel, SinaGehin, CharlotteTardivon, DelphineGeorgeon, SandrineKukenshoner, TimLoehr, FrankKoide, AkikoBuchner, LenaPanjkovich, AlejandroReynaud, AlinePinho, SaraGerig, BarbaraSvergun, DmitriPojer, FlorenceGuentert, PeterDoetsch, VolkerKoide, ShoheiGavin, Anne-ClaudeHantschel, Oliver2018-01-152018-01-152018-01-15201710.1038/s41467-017-02313-6https://infoscience.epfl.ch/handle/20.500.14299/144035WOS:000417884500007The 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.text::journal::journal article::research article