Crystal structure of EML1 reveals the basis for Hsp90 dependence of oncogenic EML4-ALK by disruption of an atypical β-propeller domain
Copyright policy )Crystal structure of EML1 reveals the basis for Hsp90 dependence of oncogenic EML4-ALK by disruption of an atypical β-propeller domain
Significance Echinoderm microtubule-associated protein (EMAP)-like (EML) proteins normally function in the cytoskeleton. In some lung cancers, genetic abnormalities generate the oncogenic fusion protein EML4-anaplastic lymphoma kinase (ALK) on which the cancer cells depend for survival. We have determined the molecular structure of a conserved, tubulin-binding region of EML1 that reveals an unexpected protein fold. This region is disrupted in ∼70% of EML4-ALK fusions found in patients, causing them to be sensitive to drugs that target Hsp90, a cellular factor that stabilizes misfolded protein. Our findings will potentially enable more effective, stratified therapy of EML4-ALK nonsmall cell lung cancer and suggest that the truncation of a globular domain at the translocation breakpoint may prove generally predictive of Hsp90 inhibitor sensitivity in cancers driven by fusion oncogenes.
- Newcastle University United Kingdom
- Institute of Cancer Research United Kingdom
- University of Leicester United Kingdom
Models, Molecular, Sequence Homology, Amino Acid, Protein Conformation, Molecular Sequence Data, Serine Endopeptidases, Receptor Protein-Tyrosine Kinases, Cell Cycle Proteins, Crystallography, X-Ray, Humans, Anaplastic Lymphoma Kinase, Amino Acid Sequence, HSP90 Heat-Shock Proteins, Microtubule-Associated Proteins
Models, Molecular, Sequence Homology, Amino Acid, Protein Conformation, Molecular Sequence Data, Serine Endopeptidases, Receptor Protein-Tyrosine Kinases, Cell Cycle Proteins, Crystallography, X-Ray, Humans, Anaplastic Lymphoma Kinase, Amino Acid Sequence, HSP90 Heat-Shock Proteins, Microtubule-Associated Proteins
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