Key result
PAS domain mutations in Kv11.1 channels impair thermostability and affect binding to the remainder of the channel, leading to severe trafficking defects in long-QT syndrome type 2.
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Mutations in the PAS domain of Kv11.1 channels cause severe trafficking defects primarily by disrupting domain-domain interactions rather than just domain unfolding, providing mechanistic insight into long-QT syndrome type 2.
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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Ke et al. (2013) studied Long-QT syndrome type 2. PAS domain mutations in Kv11.1 channels was evaluated on Domain folding and interactions between the PAS domain and the remainder of the channel. PAS domain mutations in Kv11.1 channels impair thermostability and affect binding to the remainder of the channel, leading to severe trafficking defects in long-QT syndrome type 2.
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