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Title | Structural and functional dissection of the DH and PH domains of oncogenic Bcr-Abl tyrosine kinase. |
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Journal, issue, pages | Nat Commun, Vol. 8, Issue 1, Page 2101, Year 2017 |
Publish date | Dec 13, 2017 |
![]() | Sina Reckel / Charlotte Gehin / Delphine Tardivon / Sandrine Georgeon / Tim Kükenshöner / Frank Löhr / Akiko Koide / Lena Buchner / Alejandro Panjkovich / Aline Reynaud / Sara Pinho / Barbara Gerig / Dmitri Svergun / Florence Pojer / Peter Güntert / Volker Dötsch / Shohei Koide / Anne-Claude Gavin / Oliver Hantschel / ![]() ![]() ![]() ![]() |
PubMed Abstract | 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 ...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. |
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Methods | SAS (X-ray synchrotron) / NMR (solution) / X-ray diffraction |
Resolution | 1.647 - 1.652 Å |
Structure data | ![]() SASDC26: ![]() SASDC36: ![]() SASDC46: ![]() PDB-5n6r: ![]() PDB-5n7e: ![]() PDB-5oc7: |
Chemicals | ![]() ChemComp-HOH: ![]() ChemComp-GOL: ![]() ChemComp-IP2: |
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