| Autor: |
Flores JA; Department of Chemical Physiology and Biochemistry, Oregon Health and Science University, Portland, OR, 97239, USA., Haddad BG; Department of Chemistry, Portland State University, Portland, OR, 97201, USA., Dolan KA; Department of Chemistry, Portland State University, Portland, OR, 97201, USA.; Biophysics Graduate Group, University of California, Berkeley, CA, 94720, USA., Myers JB; Department of Chemistry, Portland State University, Portland, OR, 97201, USA., Yoshioka CC; Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR, 97239, USA., Copperman J; Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR, 97239, USA., Zuckerman DM; Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR, 97239, USA., Reichow SL; Department of Chemical Physiology and Biochemistry, Oregon Health and Science University, Portland, OR, 97239, USA. reichow@pdx.edu.; Department of Chemistry, Portland State University, Portland, OR, 97201, USA. reichow@pdx.edu. |
| Abstrakt: |
Gap junctions establish direct pathways for cells to transfer metabolic and electrical messages. The local lipid environment is known to affect the structure, stability and intercellular channel activity of gap junctions; however, the molecular basis for these effects remains unknown. Here, we incorporate native connexin-46/50 (Cx46/50) intercellular channels into a dual lipid nanodisc system, mimicking a native cell-to-cell junction. Structural characterization by CryoEM reveals a lipid-induced stabilization to the channel, resulting in a 3D reconstruction at 1.9 Å resolution. Together with all-atom molecular dynamics simulations, it is shown that Cx46/50 in turn imparts long-range stabilization to the dynamic local lipid environment that is specific to the extracellular lipid leaflet. In addition, ~400 water molecules are resolved in the CryoEM map, localized throughout the intercellular permeation pathway and contributing to the channel architecture. These results illustrate how the aqueous-lipid environment is integrated with the architectural stability, structure and function of gap junction communication channels. |
