title: Molecular and structural characterization of the SH3 domain of AHI-1 in regulation of cellular resistance of BCR-ABL(+) chronic myeloid leukemia cells to tyrosine kinase inhibitors.
abstract: ABL tyrosine kinase inhibitor (TKI) therapy induces clinical remission in chronic myeloid leukemia (CML) patients but early relapses and later emergence of TKI-resistant disease remain problematic. We recently demonstrated that the AHI-1 oncogene physically interacts with BCR-ABL and JAK2 and mediates cellular resistance to TKI in CML stem/progenitor cells. We now show that deletion of the SH3 domain of AHI-1 significantly enhances apoptotic response of BCR-ABL(+) cells to TKIs compared to cells expressing full-length AHI-1. We have also discovered a novel interaction between AHI-1 and Dynamin-2, a GTPase, through the AHI-1 SH3 domain. The crystal structure of the AHI-1 SH3 domain at 1.53-Å resolution reveals that it adopts canonical SH3 folding, with the exception of an unusual C-terminal α helix. PD1R peptide, known to interact with the PI3K SH3 domain, was used to model the binding pattern between the AHI-1 SH3 domain and its ligands. These studies showed that an "Arg-Arg-Trp" stack may form within the binding interface, providing a potential target site for designing specific drugs. The crystal structure of the AHI-1 SH3 domain thus provides a valuable tool for identification of key interaction sites in regulation of drug resistance and for the development of small molecule inhibitors for CML.
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada.
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Liu
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.forename: Paolo
authors.initials: P
authors.lastname: Lobo
authors.forename: Jianghong
authors.initials: J
authors.lastname: An
authors.forename: S W
authors.initials: SW
authors.lastname: Grace Cheng
authors.forename: Annie
authors.initials: A
authors.lastname: Moradian
authors.forename: Gregg B
authors.initials: GB
authors.lastname: Morin
authors.forename: Filip
authors.initials: F
authors.lastname: Van Petegem
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Jiang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D033942:Adaptor Proteins, Vesicular Transport; D000595:Amino Acid Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D019008:Drug Resistance, Neoplasm; D034285:Dynamin II / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D013058:Mass Spectrometry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D017384:Sequence Deletion; D018909:src Homology Domains
chemical_list: C487178:AHI1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D008024:Ligands; D047428:Protein Kinase Inhibitors; D016044:Fusion Proteins, bcr-abl; D034285:Dynamin II