GONUTS has been updated to MW1.31 Most things seem to be working but be sure to report problems.

Have any questions? Please email us at ecoliwiki@gmail.com

PMID:22623184

From GONUTS
Jump to: navigation, search
Citation

Liu, X, Chen, M, Lobo, P, An, J, Grace Cheng, SW, Moradian, A, Morin, GB, Van Petegem, F and Jiang, X (2012) 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 12:2094-106

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.

Links

PubMed Online version:10.1002/pmic.201100553

Keywords

Adaptor Proteins, Signal Transducing/chemistry; Adaptor Proteins, Signal Transducing/genetics; Adaptor Proteins, Signal Transducing/metabolism; 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

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:DYN2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8N157

F

Seeded From UniProt

complete

HUMAN:AHI1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P50570

F

Seeded From UniProt

complete

See also

References

See Help:References for how to manage references in GONUTS.