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; Panjkovich, Alejandro; Reynaud, Aline; Pinho, Sara; Gerig, Barbara; Svergun, Dmitri; Pojer, Florence; Güntert, Peter; Dötsch, Volker; Koide, Shohei; Gavin Perrin, Anne-Claude; Hantschel, Oliver

doi:10.1038/s41467-017-02313-6

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Title		Structural and functional dissection of the DH and PH domains of oncogenic Bcr-Abl tyrosine kinase
Authors		Reckel, Sina Gehin, Charlotte Tardivon, Delphine Georgeon, Sandrine Kükenshöner, Tim Löhr, Frank Koide, Akiko Buchner, Lena Panjkovich, Alejandro Reynaud, Aline Pinho, Sara Gerig, Barbara Svergun, Dmitri Pojer, Florence Güntert, Peter Dötsch, Volker Koide, Shohei Gavin Perrin, Anne-Claude Hantschel, Oliver show all authors [1 - 19]
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		Carcinogenesis — Crystallography — X-Ray — Fusion Proteins — Bcr-abl/chemistry/genetics/metabolism — Humans — Leukemia/genetics/metabolism — Magnetic Resonance Spectroscopy — Models — Molecular — Pleckstrin Homology Domains — Protein Domains — Scattering — Small Angle — Signal Transduction — X-Ray Diffraction
Identifiers		DOI: 10.1038/s41467-017-02313-6 PMID: 29235475
Full text		Article (Published version) (2.4 MB) - Free access Other version: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727386/
Research groups		Métabolisme des lipides (1001) NCCR Chemical Biology
Projects		Swiss National Science Foundation: 31003A_140913 Autre: ERC-2016-CoG 682311-ONCOINTRABODY
Citation (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 https://archive-ouverte.unige.ch/unige:124440