Journal Article

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

Yoshioka, Craig C., Reichow, Steve L., Zuckerman, Daniel M., Myers, Janette B., Haddad, Bassam G., Robinson, Carol V., O’Neill, Susan E., Chorev, Dror S.

2018

Overview

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. Cryo-electron microscopy structures of connexin channels composed of connexin 46 and connexin 50 in an open-state reveal features that govern permselectivity and the location of mutated residues linked to herediatry cataracts.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 101/28 / 101/58 / 119/118 / 631/45/269 / 631/535/1258/1259 / 631/57/2266 / 631/57/2270/1140 / 631/57/2271 / 82/83 / Amino Acid Sequence / Analysis / Anchoring / Assembly / Cataract - congenital / Cataract - genetics / Cataracts / Cell interactions / Cell membranes / Cell signaling / Channels / Communication / Comparative analysis / Computer applications / Conformation / Connexin 26 / Connexin 26 - chemistry / Connexins - chemistry / Connexins - genetics / Connexins - ultrastructure / Cryoelectron Microscopy / Crystal structure / Cytological research / Electron microscopy / Gap junctions / Gap Junctions - chemistry / Gap Junctions - genetics / Gap Junctions - ultrastructure / Gene mutation / Humanities and Social Sciences / Humans / Hydrophobicity / Isoforms / Lens, Crystalline - chemistry / Lens, Crystalline - cytology / Lens, Crystalline - ultrastructure / Mass spectrometry / Microscopy / Models, Molecular / multidisciplinary / Mutation / Neurophysiology / Physiological aspects / Science / Science (multidisciplinary) / Scientific imaging / Structure-function relationships