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Title: Changes in channel trafficking and protein stability caused by LQT2 mutations in the PAS domain of the HERG channel
Authors: Harley, Carol A.
Jesus, Catarina S. H. 
Carvalho, Ricardo
Brito, Rui M. M. 
Morais-Cabral, João H.
Issue Date: 2012
Publisher: Public Library of Science
Project: European Molecular Biology Organization, EMBO (Installation Grant to JHMC) 
Ciência 2008 
Serial title, monograph or event: PLoS ONE
Volume: 7
Issue: 3
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.
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0032654
Rights: openAccess
Appears in Collections:FCTUC Química - Artigos em Revistas Internacionais
I&D CNC - Artigos em Revistas Internacionais

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