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Biophys J. 2014 Aug 5;107(3):599-612. doi: 10.1016/j.bpj.2014.05.037.

Characterization of a novel water pocket inside the human Cx26 hemichannel structure.

Author information

1
Computational Biology Lab (DLab), Fundación Ciencia & Vida, Ñuñoa, Santiago; Computational Biology Center, IBM Thomas J. Watson Research Center, Yorktown Heights, New York; Centro Interdisciplinario de Neurociencias de Valparaíso (CINV), Universidad de Valparaíso, Valparaíso.
2
Computational Biology Lab (DLab), Fundación Ciencia & Vida, Ñuñoa, Santiago; Centro Interdisciplinario de Neurociencias de Valparaíso (CINV), Universidad de Valparaíso, Valparaíso. Electronic address: tomas@dlab.cl.
3
Computational Biology Center, IBM Thomas J. Watson Research Center, Yorktown Heights, New York.
4
Computational Biology Lab (DLab), Fundación Ciencia & Vida, Ñuñoa, Santiago; Centro Interdisciplinario de Neurociencias de Valparaíso (CINV), Universidad de Valparaíso, Valparaíso.
5
Centro Interdisciplinario de Neurociencias de Valparaíso (CINV), Universidad de Valparaíso, Valparaíso.
6
Centro Interdisciplinario de Neurociencias de Valparaíso (CINV), Universidad de Valparaíso, Valparaíso; Departamento de Fisiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago.
7
Computational Biology Center, IBM Thomas J. Watson Research Center, Yorktown Heights, New York. Electronic address: ruhongz@us.ibm.com.

Abstract

Connexins (Cxs) are a family of vertebrate proteins constituents of gap junction channels (GJCs) that connect the cytoplasm of adjacent cells by the end-to-end docking of two Cx hemichannels. The intercellular transfer through GJCs occurs by passive diffusion allowing the exchange of water, ions, and small molecules. Despite the broad interest to understand, at the molecular level, the functional state of Cx-based channels, there are still many unanswered questions regarding structure-function relationships, perm-selectivity, and gating mechanisms. In particular, the ordering, structure, and dynamics of water inside Cx GJCs and hemichannels remains largely unexplored. In this work, we describe the identification and characterization of a believed novel water pocket-termed the IC pocket-located in-between the four transmembrane helices of each human Cx26 (hCx26) monomer at the intracellular (IC) side. Using molecular dynamics (MD) simulations to characterize hCx26 internal water structure and dynamics, six IC pockets were identified per hemichannel. A detailed characterization of the dynamics and ordering of water including conformational variability of residues forming the IC pockets, together with multiple sequence alignments, allowed us to propose a functional role for this cavity. An in vitro assessment of tracer uptake suggests that the IC pocket residue Arg-143 plays an essential role on the modulation of the hCx26 hemichannel permeability.

PMID:
25099799
PMCID:
PMC4129493
DOI:
10.1016/j.bpj.2014.05.037
[Indexed for MEDLINE]
Free PMC Article

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