1. Kinase Regulation by Hydrophobic Spine Assembly in Cancer
- Author
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Hu, Jiancheng, Ahuja, Lalima G, Meharena, Hiruy S, Kannan, Natarajan, Kornev, Alexandr P, Taylor, Susan S, and Shaw, Andrey S
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Biological Sciences ,Cancer ,Adenosine Triphosphate ,Allosteric Site ,Catalysis ,ErbB Receptors ,Gene Expression Regulation ,Neoplastic ,HEK293 Cells ,Histidine ,Humans ,Hydrophobic and Hydrophilic Interactions ,Methionine ,Models ,Molecular ,Mutation ,Neoplasms ,Phosphotransferases ,Protein Structure ,Secondary ,Proto-Oncogene Proteins B-raf ,Proto-Oncogene Proteins c-abl ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
A new model of kinase regulation based on the assembly of hydrophobic spines has been proposed. Changes in their positions can explain the mechanism of kinase activation. Here, we examined mutations in human cancer for clues about the regulation of the hydrophobic spines by focusing initially on mutations to Phe. We identified a selected number of Phe mutations in a small group of kinases that included BRAF, ABL1, and the epidermal growth factor receptor. Testing some of these mutations in BRAF, we found that one of the mutations impaired ATP binding and catalytic activity but promoted noncatalytic allosteric functions. Other Phe mutations functioned to promote constitutive catalytic activity. One of these mutations revealed a previously underappreciated hydrophobic surface that functions to position the dynamic regulatory αC-helix. This supports the key role of the C-helix as a signal integration motif for coordinating multiple elements of the kinase to create an active conformation. The importance of the hydrophobic space around the αC-helix was further tested by studying a V600F mutant, which was constitutively active in the absence of the negative charge that is associated with the common V600E mutation. Many hydrophobic mutations strategically localized along the C-helix can thus drive kinase activation.
- Published
- 2015