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Cryo-EM structure of the volume-regulated anion channel LRRC8D isoform identifies features important for substrate permeation

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Item Type:Article
Title:Cryo-EM structure of the volume-regulated anion channel LRRC8D isoform identifies features important for substrate permeation
Creators Name:Nakamura, R. and Numata, T. and Kasuya, G. and Yokoyama, T. and Nishizawa, T. and Kusakizako, T. and Kato, T. and Hagino, T. and Dohmae, N. and Inoue, M. and Watanabe, K. and Ichijo, H. and Kikkawa, M. and Shirouzu, M. and Jentsch, T.J. and Ishitani, R. and Okada, Y. and Nureki, O.
Abstract:Members of the leucine-rich repeat-containing 8 (LRRC8) protein family, composed of the five LRRC8A-E isoforms, are pore-forming components of the volume-regulated anion channel (VRAC). LRRC8A and at least one of the other LRRC8 isoforms assemble into heteromers to generate VRAC transport activities. Despite the availability of the LRRC8A structures, the structural basis of how LRRC8 isoforms other than LRRC8A contribute to the functional diversity of VRAC has remained elusive. Here, we present the structure of the human LRRC8D isoform, which enables the permeation of organic substrates through VRAC. The LRRC8D homo-hexamer structure displays a two-fold symmetric arrangement, and together with a structure-based electrophysiological analysis, revealed two key features. The pore constriction on the extracellular side is wider than that in the LRRC8A structures, which may explain the increased permeability of organic substrates. Furthermore, an N-terminal helix protrudes into the pore from the intracellular side and may be critical for gating.
Source:Communications Biology
ISSN:2399-3642
Publisher:Nature Publishing Group
Volume:3
Number:1
Page Range:240
Date:15 May 2020
Official Publication:https://doi.org/10.1038/s42003-020-0951-z
PubMed:View item in PubMed

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