PT  - JOURNAL ARTICLE
AU  - Marina A. Kasimova
AU  - Aysenur Torun Yazici
AU  - Yevgen Yudin
AU  - Daniele Granata
AU  - Michael L. Klein
AU  - Tibor Rohacs
AU  - Vincenzo Carnevale
TI  - A consistent picture of TRPV1 activation emerges from molecular simulations and experiments
AID  - 10.1101/310151
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 310151
4099  - http://biorxiv.org/content/early/2018/08/24/310151.short
4100  - http://biorxiv.org/content/early/2018/08/24/310151.full
AB  - Although the structure of TRPV1 has been experimentally determined in both the closed and open states, very little is known about its activation mechanism. In particular, the conformational changes occurring in the pore domain and resulting in ionic conduction have not been identified yet. Here, we suggest a hypothetical molecular mechanism for TRPV1 activation, which involves the rotation of a conserved asparagine in S6 from the S4-S5 linker toward the pore. This rotation is correlated with the dehydration of four peripheral cavities located between S6 and the S4-S5 linker and the hydration of the pore. In light of our hypothesis, we perform bioinformatics analyses of TRP and other evolutionary related ion channels, analyze newly available structures and re-examine previously reported water accessibility and mutagenesis experiments. Overall, we provide several independent lines of evidence that corroborate our hypothesis. Finally, we show that the proposed molecular mechanism is compatible with the currently existing idea that in TRPV1 the selectivity filter acts as a secondary gate.