Séminaire additionnel du Workshop ADTB 2019 : How HCN channels activate : when structure, dynamics and function come together

Orateur : Lucie DELEMOTTE (KTH Royal Institute of Technology, Stockholm)

Voltage-gated ion channels are the membrane proteins whose opening and closing are responsible for the propagation of action potentials in excitable cells. Their dysfunction leads to diseases such as cardiac arrhythmias, epilepsy or muscle ataxia. As such, they constitute major drug targets.HCN channels, unlike other members of the voltage-gated ion channel superfamily, open upon hyperpolarization rather than depolarization. Their structure is in large part similar to the ones of other family members. How is their peculiar function then encoded ? We use long all-atom molecular dynamics simulations under hyperpolarization conditions to probe this question, and reveal an unexpected mechanism of inward rectification. The simulations show that a single serine residue located in a key transmembrane helix plays a crucial role by allowing helix breaking during channel response. We test this hypothesis using cysteine accessibility measurements and electrophysiology recordings in carefully chosen mutants. We ultimately confirm that a single point mutation of this conserved residue can flip the gating polarity of chimeric channels, revealing a possible novel trajectory for voltage-gated ion channel evolution.

Télécharger dans mon agenda