Loss of Kv11.1 potassium channel function is the underlying cause of pathology in long-QT syndrome type 2, one of the commonest causes of sudden cardiac death in the young. Previous studies have identified the cytosolic PAS (Per/Arnt/Sim) domain as a hotspot for mutations that cause Kv11.1 trafficking defects. To investigate the underlying basis of this observation, we have quantified the effect of mutants on domain folding as well as interactions between the PAS domain and the remainder of the channel. Apart from R56Q, all mutants impaired the thermostability of the isolated PAS domain. Six mutants, located in the vicinity of a hydrophobic patch on the PAS domain surface, also affected binding of the isolated PAS domain to an N-terminal truncated hERG (human ether-a-go-go-related gene) channel. Conversely, four other surface mutants (C64Y, T65P, A78P and I96T) and one buried mutant (L86R) did not prevent the isolated PAS domain binding to the truncated channels. Our results highlight a critical role for interactions between the PAS domain and the remainder of the channel in the hERG assembly and that mutants that affect PAS domain interactions with the remainder of the channel have a more severe trafficking defect than that caused by domain unfolding alone.
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Research Article|
July 26 2013
Trafficking defects in PAS domain mutant Kv11.1 channels: roles of reduced domain stability and altered domain–domain interactions
Ying Ke;
Ying Ke
*Mark Cowley Lidwill Research Program in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia
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Chai Ann Ng;
Chai Ann Ng
*Mark Cowley Lidwill Research Program in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia
†St Vincent's Clinical School, University of New South Wales, Victoria Street, Darlinghurst, NSW 2010, Australia
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Mark J. Hunter;
Mark J. Hunter
*Mark Cowley Lidwill Research Program in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia
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Stefan A. Mann;
Stefan A. Mann
*Mark Cowley Lidwill Research Program in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia
†St Vincent's Clinical School, University of New South Wales, Victoria Street, Darlinghurst, NSW 2010, Australia
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Juliane Heide;
Juliane Heide
*Mark Cowley Lidwill Research Program in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia
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Adam P. Hill;
Adam P. Hill
*Mark Cowley Lidwill Research Program in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia
†St Vincent's Clinical School, University of New South Wales, Victoria Street, Darlinghurst, NSW 2010, Australia
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Jamie I. Vandenberg
Jamie I. Vandenberg
1
*Mark Cowley Lidwill Research Program in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia
†St Vincent's Clinical School, University of New South Wales, Victoria Street, Darlinghurst, NSW 2010, Australia
1To whom correspondence should be addressed (email j.vandenberg@victorchang.edu.au).
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Publisher: Portland Press Ltd
Received:
March 01 2013
Revision Received:
May 13 2013
Accepted:
May 31 2013
Accepted Manuscript online:
May 31 2013
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2013 Biochemical Society
2013
Biochem J (2013) 454 (1): 69–77.
Article history
Received:
March 01 2013
Revision Received:
May 13 2013
Accepted:
May 31 2013
Accepted Manuscript online:
May 31 2013
Citation
Ying Ke, Chai Ann Ng, Mark J. Hunter, Stefan A. Mann, Juliane Heide, Adam P. Hill, Jamie I. Vandenberg; Trafficking defects in PAS domain mutant Kv11.1 channels: roles of reduced domain stability and altered domain–domain interactions. Biochem J 15 August 2013; 454 (1): 69–77. doi: https://doi.org/10.1042/BJ20130328
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