Structure of native lens connexin 46/50 intercellular channels by cryo-EM

Nature. 2018 Dec;564(7736):372-377. doi: 10.1038/s41586-018-0786-7. Epub 2018 Dec 12.

Abstract

Gap junctions establish direct pathways for cell-to-cell communication through the assembly of twelve connexin subunits that form intercellular channels connecting neighbouring cells. Co-assembly of different connexin isoforms produces channels with unique properties and enables communication across cell types. Here we used single-particle cryo-electron microscopy to investigate the structural basis of connexin co-assembly in native lens gap junction channels composed of connexin 46 and connexin 50 (Cx46/50). We provide the first comparative analysis to connexin 26 (Cx26), which-together with computational studies-elucidates key energetic features governing gap junction permselectivity. Cx46/50 adopts an open-state conformation that is distinct from the Cx26 crystal structure, yet it appears to be stabilized by a conserved set of hydrophobic anchoring residues. 'Hot spots' of genetic mutations linked to hereditary cataract formation map to the core structural-functional elements identified in Cx46/50, suggesting explanations for many of the disease-causing effects.

MeSH terms

  • Amino Acid Sequence
  • Cataract / congenital
  • Cataract / genetics
  • Connexin 26 / chemistry
  • Connexins / chemistry*
  • Connexins / genetics
  • Connexins / ultrastructure*
  • Cryoelectron Microscopy*
  • Gap Junctions / chemistry
  • Gap Junctions / genetics
  • Gap Junctions / ultrastructure
  • Humans
  • Lens, Crystalline / chemistry
  • Lens, Crystalline / cytology*
  • Lens, Crystalline / ultrastructure*
  • Models, Molecular
  • Mutation

Substances

  • Connexins
  • connexin 46
  • connexin 50
  • Connexin 26