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

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...

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Veröffentlicht in:Nature (London) 2018-12, Vol.564 (7736), p.372-377
Hauptverfasser: Myers, Janette B., Haddad, Bassam G., O’Neill, Susan E., Chorev, Dror S., Yoshioka, Craig C., Robinson, Carol V., Zuckerman, Daniel M., Reichow, Steve L.
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container_issue 7736
container_start_page 372
container_title Nature (London)
container_volume 564
creator Myers, Janette B.
Haddad, Bassam G.
O’Neill, Susan E.
Chorev, Dror S.
Yoshioka, Craig C.
Robinson, Carol V.
Zuckerman, Daniel M.
Reichow, Steve L.
description 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.
doi_str_mv 10.1038/s41586-018-0786-7
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subjects 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
title Structure of native lens connexin 46/50 intercellular channels by cryo-EM
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