5n7e
From Proteopedia
Crystal structure of the Dbl-homology domain of Bcr-Abl in complex with monobody Mb(Bcr-DH_4).
Structural highlights
DiseaseBCR_HUMAN Note=A chromosomal aberration involving BCR is a cause of chronic myeloid leukemia. Translocation t(9;22)(q34;q11) with ABL1. The translocation produces a BCR-ABL found also in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). FunctionBCR_HUMAN GTPase-activating protein for RAC1 and CDC42. Promotes the exchange of RAC or CDC42-bound GDP by GTP, thereby activating them. Displays serine/threonine kinase activity.[1] [2] Publication Abstract from PubMedThe 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. Structural and functional dissection of the DH and PH domains of oncogenic Bcr-Abl tyrosine kinase.,Reckel S, Gehin C, Tardivon D, Georgeon S, Kukenshoner T, Lohr F, Koide A, Buchner L, Panjkovich A, Reynaud A, Pinho S, Gerig B, Svergun D, Pojer F, Guntert P, Dotsch V, Koide S, Gavin AC, Hantschel O Nat Commun. 2017 Dec 13;8(1):2101. doi: 10.1038/s41467-017-02313-6. PMID:29235475[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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