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

Proteomics. 2012 Jul;12(13):2094-106. doi: 10.1002/pmic.201100553.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry*
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Adaptor Proteins, Vesicular Transport
  • Amino Acid Sequence
  • Binding Sites
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • Drug Resistance, Neoplasm*
  • Dynamin II / metabolism
  • Fusion Proteins, bcr-abl / antagonists & inhibitors
  • Fusion Proteins, bcr-abl / metabolism*
  • Humans
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
  • Ligands
  • Mass Spectrometry
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Structure, Secondary
  • Sequence Alignment
  • Sequence Deletion
  • src Homology Domains*


  • AHI1 protein, human
  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • Ligands
  • Protein Kinase Inhibitors
  • Fusion Proteins, bcr-abl
  • Dynamin II