Symmetry-driven gating of TRPM8 by PIP2 and menthol
Kim, Sun-Hong
;
Hong, Chansik
;
Park, Hyunwoo
;
Ju, Youngchang
;
Hwang, Youngsoo
;
Kim, Jinhyeong
;
Ji, Sangho
;
Yu, Wookyung
;
So, Insuk
;
Lee, Hyung Ho
TRPM8, a cold-activated ion channel, enables mammals to sense cooling agents such as menthol. While PIP2 is essential for menthol-induced activation of TRPM8, the precise cooperative mechanism and the specific binding mode of menthol have remained elusive. Here, we present cryo-EM structures of mouse TRPM8 in diverse conformations, including a PIP2-induced two-fold symmetric intermediate and an icilin-bound open state. Our results reveal that PIP2 binding initiates a symmetry-breaking event, pri