Connexin 46 and connexin 50 gap junction channel open stability and unitary conductance are shaped by structural and dynamic features of their N-terminal domains

摘要: The connexins form intercellular communication channels, known as gap junctions (GJs), that facilitate diverse physiological roles in vertebrate species, ranging from electrical coupling and long-range chemical signaling, to coordinating development nutrient exchange. GJs formed by different are expressed throughout the body harbor unique channel properties have not been fully defined mechanistically. Recent structural studies implicated amino-terminal (NT) domain contributing isoform-specific functional differences exist between lens connexins, Cx50 Cx46. To better understand two closely related, yet functionally distinct GJs, we constructed models corresponding CryoEM-based structures of wildtype Cx46 NT swapped chimeras (Cx46-50NT Cx50-46NT), point variants at 9th residue (Cx46-R9N Cx50-N9R) for comparative MD simulation electrophysiology studies. All these constructs GJ except Cx46-50NT, which correlated with increased dynamical behavior (instability) observed simulation. Single conductance ({gamma}j) also well free-energy landscapes predicted MD, where {gamma}j Cx46-R9N was {gamma}js Cx50-46NT Cx50-N9R decreased Cx50, but a surprisingly greater degree. Additionally, significant effects on transjunctional voltage-dependent gating (Vj-gating) open-state dwell times induced designed variants. Together, indicate domains play an important role defining related stability single conductance.