National Natural Science Foundation of China (NSFC)
81872915
中国
National Natural Science Foundation of China (NSFC)
82073904
中国
National Natural Science Foundation of China (NSFC)
82121005
中国
National Natural Science Foundation of China (NSFC)
81973373
中国
National Natural Science Foundation of China (NSFC)
21704064
中国
Other government
2018ZX09735-001
中国
Other government
2018ZX09711002-002-005
中国
Other government
2021ZD0203400
中国
Other government
2018YFA0507000
中国
Other government
ZDKJ2021028
中国
Other private
NNCAS-2017-1-CC
中国
National Institutes of Health/National Cancer Institute (NIH/NCI)
R35 CA197582
米国
National Institutes of Health/National Cancer Institute (NIH/NCI)
R50 CA243899
米国
引用
ジャーナル: Proc Natl Acad Sci U S A / 年: 2022 タイトル: Cryo-EM structures of cancer-specific helical and kinase domain mutations of PI3Kα. 著者: Xiao Liu / Qingtong Zhou / Jonathan R Hart / Yingna Xu / Su Yang / Dehua Yang / Peter K Vogt / Ming-Wei Wang / 要旨: Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that perform multiple and important cellular functions. The protein investigated here belongs to class IA of the PI3Ks; it is a dimer ...Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that perform multiple and important cellular functions. The protein investigated here belongs to class IA of the PI3Ks; it is a dimer consisting of a catalytic subunit, p110α, and a regulatory subunit, p85α, and is referred to as PI3Kα. The catalytic subunit p110α is frequently mutated in cancer. The mutations induce a gain of function and constitute a driving force in cancer development. About 80% of these mutations lead to single-amino-acid substitutions in one of three sites of p110α: two in the helical domain of the protein (E542K and E545K) and one at the C-terminus of the kinase domain (H1047R). Here, we report the cryo-electron microscopy structures of these mutants in complex with the p110α-specific inhibitor BYL-719. The H1047R mutant rotates its sidechain to a new position and weakens the kα11 activation loop interaction, thereby reducing the inhibitory effect of p85α on p110α. E542K and E545K completely abolish the tight interaction between the helical domain of p110α and the N-terminal SH2 domain of p85α and lead to the disruption of all p85α binding and a dramatic increase in flexibility of the adaptor-binding domain (ABD) in p110α. Yet, the dimerization of PI3Kα is preserved through the ABD-p85α interaction. The local and global structural features induced by these mutations provide molecular insights into the activation of PI3Kα, deepen our understanding of the oncogenic mechanism of this important signaling molecule, and may facilitate the development of mutant-specific inhibitors.