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Kinase regulation by hydrophobic spine assembly in cancer
#MMPMID25348715
Hu J
; Ahuja LG
; Meharena HS
; Kannan N
; Kornev AP
; Taylor SS
; Shaw AS
Mol Cell Biol
2015[Jan]; 35
(1
): 264-76
PMID25348715
show ga
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 ?C-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 ?C-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.
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