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https://hdl.handle.net/10316/109924
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) SFRH/BD/43896/2008 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. | URI: | http://hdl.handle.net/10316/109924 | 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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