TY - JOUR
T1 - Structural Basis of a Kv7.1 Potassium Channel Gating Module
T2 - Studies of the Intracellular C-Terminal Domain in Complex with Calmodulin
AU - Sachyani, Dana
AU - Dvir, Meidan
AU - Strulovich, Roi
AU - Tria, Giancarlo
AU - Tobelaim, William
AU - Peretz, Asher
AU - Pongs, Olaf
AU - Svergun, Dmitri
AU - Attali, Bernard
AU - Hirsch, Joel A.
N1 - Publisher Copyright:
© 2014 Elsevier Ltd.
PY - 2014/11/4
Y1 - 2014/11/4
N2 - Kv7 channels tune neuronal and cardiomyocyte excitability. In addition to the channel membrane domain, they also have a unique intracellular C-terminal (CT) domain, bound constitutively to calmodulin (CaM). This CT domain regulates gating and tetramerization. We investigated the structure of the membrane proximal CT module in complex with CaM by X-ray crystallography. The results show how the CaM intimately hugs a two-helical bundle, explaining many channelopathic mutations. Structure-based mutagenesis of this module in the context of concatemeric tetramer channels and functional analysis along with in vitro data lead us to propose that one CaM binds to one individual protomer, without crosslinking subunits and that this configuration is required for proper channel expression and function. Molecular modeling of the CT/CaM complex in conjunction with small-angle X-ray scattering suggests that the membrane proximal region, having a rigid lever arm, is a critical gating regulator.
AB - Kv7 channels tune neuronal and cardiomyocyte excitability. In addition to the channel membrane domain, they also have a unique intracellular C-terminal (CT) domain, bound constitutively to calmodulin (CaM). This CT domain regulates gating and tetramerization. We investigated the structure of the membrane proximal CT module in complex with CaM by X-ray crystallography. The results show how the CaM intimately hugs a two-helical bundle, explaining many channelopathic mutations. Structure-based mutagenesis of this module in the context of concatemeric tetramer channels and functional analysis along with in vitro data lead us to propose that one CaM binds to one individual protomer, without crosslinking subunits and that this configuration is required for proper channel expression and function. Molecular modeling of the CT/CaM complex in conjunction with small-angle X-ray scattering suggests that the membrane proximal region, having a rigid lever arm, is a critical gating regulator.
UR - http://www.scopus.com/inward/record.url?scp=84908546275&partnerID=8YFLogxK
U2 - 10.1016/j.str.2014.07.016
DO - 10.1016/j.str.2014.07.016
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
C2 - 25441029
AN - SCOPUS:84908546275
SN - 0969-2126
VL - 22
SP - 1582
EP - 1594
JO - Structure
JF - Structure
IS - 11
ER -