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


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.

Submission Details

ID: JRZnyr2X4

Submitter: Shu-Ching Ou

Submission Date: Dec. 11, 2018, 12:21 p.m.

Version: 1

Publication Details
Harley CA;Jesus CS;Carvalho R;Brito RM;Morais-Cabral JH,PLoS One (2012) Changes in channel trafficking and protein stability caused by LQT2 mutations in the PAS domain of the HERG channel. PMID:22396785
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