TY - JOUR
T1 - Voltage-dependent conformational changes in connexin channels
AU - Bargiello, Thaddeus A.
AU - Tang, Qingxiu
AU - Oh, Seunghoon
AU - Kwon, Taekyung
N1 - Funding Information:
This work was supported by NIH grant R01GM46889 to TAB. Additional support was provided by the Albert Einstein College of Medicine . Computational resources were provided by the Division of High Performance and Research Computing at UMDNJ and by the National Science Foundation through TeraGrid resources provided by NCSA under grant number TG- IBN090012 and by the HPC Core Service at Albert Einstein College of Medicine . We are grateful to Drs. Andrew Harris and Benoit Roux and their laboratories for discussion and insights.
PY - 2012/8
Y1 - 2012/8
N2 - Channels formed by connexins display two distinct types of voltage-dependent gating, termed Vj- or fast-gating and loop- or slow-gating. Recent studies, using metal bridge formation and chemical cross-linking have identified a region within the channel pore that contributes to the formation of the loop-gate permeability barrier. The conformational changes are remarkably large, reducing the channel pore diameter from 15 to 20 Å to less than 4 Å. Surprisingly, the largest conformational change occurs in the most stable region of the channel pore, the 310 or parahelix formed by amino acids in the 42-51 segment. The data provide a set of positional constraints that can be used to model the structure of the loop-gate closed state. Less is known about the conformation of the Vj-gate closed state. There appear to be two different mechanisms; one in which conformational changes in channel structure are linked to a voltage sensor contained in the N-terminus of Cx26 and Cx32 and a second in which the C-terminus of Cx43 and Cx40 may act either as a gating particle to block the channel pore or alternatively to stabilize the closed state. The later mechanism utilizes the same domains as implicated in effecting pH gating of Cx43 channels. It is unclear if the two Vj-gating mechanisms are related or if they represent different gating mechanisms that operate separately in different subsets of connexin channels. A model of the Vj-closed state of Cx26 hemichannel that is based on the X-ray structure of Cx26 and electron crystallographic structures of a Cx26 mutation suggests that the permeability barrier for Vj-gating is formed exclusively by the N-terminus, but recent information suggests that this conformation may not represent a voltage-closed state. Closed state models are considered from a thermodynamic perspective based on information from the 3.5 Å Cx26 crystal structure and molecular dynamics (MD) simulations. The applications of computational and experimental methods to define the path of allosteric molecular transitions that link the open and closed states are discussed. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.
AB - Channels formed by connexins display two distinct types of voltage-dependent gating, termed Vj- or fast-gating and loop- or slow-gating. Recent studies, using metal bridge formation and chemical cross-linking have identified a region within the channel pore that contributes to the formation of the loop-gate permeability barrier. The conformational changes are remarkably large, reducing the channel pore diameter from 15 to 20 Å to less than 4 Å. Surprisingly, the largest conformational change occurs in the most stable region of the channel pore, the 310 or parahelix formed by amino acids in the 42-51 segment. The data provide a set of positional constraints that can be used to model the structure of the loop-gate closed state. Less is known about the conformation of the Vj-gate closed state. There appear to be two different mechanisms; one in which conformational changes in channel structure are linked to a voltage sensor contained in the N-terminus of Cx26 and Cx32 and a second in which the C-terminus of Cx43 and Cx40 may act either as a gating particle to block the channel pore or alternatively to stabilize the closed state. The later mechanism utilizes the same domains as implicated in effecting pH gating of Cx43 channels. It is unclear if the two Vj-gating mechanisms are related or if they represent different gating mechanisms that operate separately in different subsets of connexin channels. A model of the Vj-closed state of Cx26 hemichannel that is based on the X-ray structure of Cx26 and electron crystallographic structures of a Cx26 mutation suggests that the permeability barrier for Vj-gating is formed exclusively by the N-terminus, but recent information suggests that this conformation may not represent a voltage-closed state. Closed state models are considered from a thermodynamic perspective based on information from the 3.5 Å Cx26 crystal structure and molecular dynamics (MD) simulations. The applications of computational and experimental methods to define the path of allosteric molecular transitions that link the open and closed states are discussed. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.
KW - Cadmium metal-bridge
KW - Gap junction
KW - Ion channel
KW - Molecular dynamics
KW - Structure-function
KW - Voltage-dependent gating
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U2 - 10.1016/j.bbamem.2011.09.019
DO - 10.1016/j.bbamem.2011.09.019
M3 - Review article
C2 - 21978595
AN - SCOPUS:84861618268
SN - 0005-2736
VL - 1818
SP - 1807
EP - 1822
JO - Biochimica et Biophysica Acta - Biomembranes
JF - Biochimica et Biophysica Acta - Biomembranes
IS - 8
ER -