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
- 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.
MetadatenAuthor: | Sina Reckel, Charlotte Gehin, Delphine Tardivon, Sandrine Georgeon, Tim Kükenshöner, Frank LöhrORCiD, Akiko Koide, Lena Buchner, Alejandro Panjkovich, Aline Reynaud, Sara Pinho, Barbara Gerig, Dmitri Svergun, Florence Pojer, Peter GüntertORCiDGND, Volker DötschORCiDGND, Shohei Koide, Anne-Claude Gavin, Oliver Hantschel |
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URN: | urn:nbn:de:hebis:30:3-456101 |
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DOI: | https://doi.org/10.1038/s41467-017-02313-6 |
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ISSN: | 2041-1723 |
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Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/29235475 |
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Parent Title (English): | Nature Communications |
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Publisher: | Nature Publishing Group UK |
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Place of publication: | [London] |
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Document Type: | Article |
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Language: | English |
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Year of Completion: | 2017 |
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Date of first Publication: | 2017/12/13 |
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Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Release Date: | 2018/02/01 |
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Tag: | Kinases; SAXS; Solution-state NMR; X-ray crystallography |
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Volume: | 8 |
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Issue: | 1, Art. 2101 |
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Page Number: | 14 |
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First Page: | 1 |
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Last Page: | 14 |
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Note: | Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/. © The Author(s) 2017 |
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HeBIS-PPN: | 426623991 |
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Institutes: | Biochemie, Chemie und Pharmazie / Biochemie und Chemie |
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| Exzellenzcluster / Exzellenzcluster Makromolekulare Komplexe |
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| Wissenschaftliche Zentren und koordinierte Programme / Zentrum für Biomolekulare Magnetische Resonanz (BMRZ) |
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Dewey Decimal Classification: | 5 Naturwissenschaften und Mathematik / 54 Chemie / 540 Chemie und zugeordnete Wissenschaften |
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Sammlungen: | Universitätspublikationen |
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Licence (German): | Creative Commons - Namensnennung 4.0 |
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