Abstract
Connexin channels play numerous essential roles in virtually every organ by mediating solute exchange between adjacent cells, or between cytoplasm and extracellular milieu. Our understanding of the structure-function relationship of connexin channels relies on X-ray crystallographic data for human connexin 26 (hCx26) intercellular gap junction channels. Comparison of experimental data and molecular dynamics simulations suggests that the published structures represent neither fully-open nor closed configurations. To facilitate the search for alternative stable configurations, we developed a coarse grained (CG) molecular model of the hCx26 hemichannel and studied its responses to external electric fields. When challenged by a field of 0.06 V/nm, the hemichannel relaxed toward a novel configuration characterized by a widened pore and an increased bending of the second transmembrane helix (TM2) at the level of the conserved Pro87. A point mutation that inhibited such transition in our simulations impeded hemichannel opening in electrophysiology and dye uptake experiments conducted on HeLa tranfectants. These results suggest that the hCx26 hemichannel uses a global degree of freedom to transit between different configuration states, which may be shared among the whole connexin family.
Highlights
Connexins are topologically conserved proteins composed of four transmembrane (TM) helixes connected by two extracellular loops (EC1, EC2) and one cytoplasmic (CL) loop
coarse grained (CG) simulations were performed using the SIRAH force field (Darré et al, 2015), which is sensitive to variations in ionic strength and protein sequence (Surdo et al, 2017), and the lipid parameterization presented in Astrada et al (2016)
The minimum pore diameters of the X-ray crystallographic structures, the AA and CG models are indistinguishable from each other (Figure 1E), once statistical fluctuations and experimental resolution are taken into account
Summary
Connexins are topologically conserved proteins composed of four transmembrane (TM) helixes connected by two extracellular loops (EC1, EC2) and one cytoplasmic (CL) loop. Known as connexons, are hexameric arrays of connexins They can function as regular membrane channels (Bennett et al, 2003; Sáez and Leybaert, 2014), or dock in the extracellular space to form gap junction channels that support direct cell-to-cell communication by connecting adjacent cytoplasmic spaces (Goodenough and Paul, 2009). The relevance of connexins and their tightly regulated function is highlighted by their implication in pathological states of completely different character, such as cancer (Tsai et al, 2018), inflammation (Li et al, 2018), and neurodegenerative diseases (Belousov et al, 2018) For this reason, modulation of connexin hemichannels is becoming increasingly interesting for the treatment of several diseases including Alzheimer Disease (Yi et al, 2017), skin disorders, or X-linked Charcot Marie Tooth disease (Sáez and Leybaert, 2014; Carrer et al, 2017; Xu et al, 2017)
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