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Structural and functional dissection of the DH and PH domains of oncogenic Bcr-Abl tyrosine kinase

Reckel, Sina
Gehin, Charlotte
Tardivon, Delphine
Georgeon, Sandrine
Kükenshöner, Tim
Löhr, Frank
Koide, Akiko
Buchner, Lena
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Published in Nature communications. 2017, vol. 8, no. 1, 2101
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 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.
Keywords CarcinogenesisCrystallographyX-RayFusion ProteinsBcr-abl/chemistry/genetics/metabolismHumansLeukemia/genetics/metabolismMagnetic Resonance SpectroscopyModelsMolecularPleckstrin Homology DomainsProtein DomainsScatteringSmall AngleSignal TransductionX-Ray Diffraction
PMID: 29235475
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Research groups Métabolisme des lipides (1001)
NCCR Chemical Biology
Swiss National Science Foundation: 31003A_140913
Autre: ERC-2016-CoG 682311-ONCOINTRABODY
(ISO format)
RECKEL, Sina et al. Structural and functional dissection of the DH and PH domains of oncogenic Bcr-Abl tyrosine kinase. In: Nature Communications, 2017, vol. 8, n° 1, p. 2101. doi: 10.1038/s41467-017-02313-6

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Deposited on : 2019-10-15

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