Referenced in: none

Automatically associated channels: Kv11.1 , Kv7.1

Title: Changes in channel trafficking and protein stability caused by LQT2 mutations in the PAS domain of the HERG channel.

Authors: Carol A Harley, Catarina S H Jesus, Ricardo Carvalho, Rui M M Brito, João H Morais-Cabral

Journal, date & volume: PLoS ONE, 2012 , 7, e32654

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/22396785

Abstract
Inherited human long-QT2 syndrome (LQTS) results from mutations in the gene encoding the HERG channel. Several LQT2-associated mutations have been mapped to the amino terminal cytoplasmic Per-Arnt-Sim (PAS) domain of the HERG1a channel subunit. Here we have characterized the trafficking properties of some LQT2-associated PAS domain mutants and analyzed rescue of the trafficking mutants by low temperature (27°C) or by the pore blocker drug E4031. We show that the LQT2-associated mutations in the PAS domain of the HERG channel display molecular properties that are distinct from the properties of LQT2-associated mutations in the trans-membrane region. Unlike the latter, many of the tested PAS domain LQT2-associated mutations do not result in trafficking deficiency of the channel. Moreover, the majority of the PAS domain mutations that cause trafficking deficiencies are not rescued by a pore blocking drug. We have also explored the in vitro folding stability properties of isolated mutant PAS domain proteins using a thermal unfolding fluorescence assay and a chemical unfolding assay.