Tracking a complete voltage-sensor cycle with metal-ion bridges
2012 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 22, 8552-8557 p.Article in journal (Refereed) Published
Voltage-gated ion channels open and close in response to changes in membrane potential, thereby enabling electrical signaling in excitable cells. The voltage sensitivity is conferred through four voltage-sensor domains (VSDs) where positively charged residues in the fourth transmembrane segment (S4) sense the potential. While an open state is known from the Kv1.2/2.1 X-ray structure, the conformational changes underlying voltage sensing have not been resolved. We present 20 additional interactions in one open and four different closed conformations based on metal-ion bridges between all four segments of the VSD in the voltage-gated Shaker K channel. A subset of the experimental constraints was used to generate Rosetta models of the conformations that were subjected to molecular simulation and tested against the remaining constraints. This achieves a detailed model of intermediate conformations during VSD gating. The results provide molecular insight into the transition, suggesting that S4 slides at least 12 angstrom along its axis to open the channel with a 3(10) helix region present that moves in sequence in S4 in order to occupy the same position in space opposite F290 from open through the three first closed states.
Place, publisher, year, edition, pages
National Academy of Sciences , 2012. Vol. 109, no 22, 8552-8557 p.
electrophysiology, inactivation, Xenopus oocytes, voltage clamp, conformational transition
National CategoryMedical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-78812DOI: 10.1073/pnas.1116938109ISI: 000304881700044OAI: oai:DiVA.org:liu-78812DiVA: diva2:536044
Funding Agencies|Swedish Research Council||Swedish Heart-Lung Foundation||Swedish Brain Foundation||County Council of Ostergotland||Queen Silvias Anniversary Foundation||King Gustaf V and Queen Victorias Freemasons Foundation||Stina and Birger Johanssons Foundation||Swedish Society for Medical Research||Swedish Foundation for Strategic Research||European Research Council||2012-06-212012-06-212013-10-15