Ke, Ying and Ng, Chai Ann and Hunter, Mark J and Mann, Stefan A and Heide, Juliane and Hill, Adam P and Vandenberg, Jamie I (2013) Trafficking defects in PAS domain mutant Kv11.1 channels: roles of reduced domain stability and altered domain-domain interactions. The Biochemical journal, 454 (1). pp.69-77. ISSN 1470-8728 (OA)
Full text not available from this repository.Abstract
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.
(NHMRC grants 573715, 1019693; National Heart Foundation of Australia grant G11S 5829; ARC Future Fellowship grant FT110100075).
| Item Type: | Article |
|---|---|
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 22 Dec 2015 02:37 |
| Last Modified: | 25 Jan 2016 00:19 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/56 |
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