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
Additional Information

Structure view and single mutant data analysis

Study data

No weblogo for data of varying length.
Colors: D E R H K S T N Q A V I L M F Y W C G P
 

Data Distribution

Studies with similar sequences (approximate matches)

Correlation with other assays (exact sequence matches)


Relevant PDB Entries

Structure ID Release Date Resolution Structure Title
2N7G 2016-05-18 Structure of the cyclic nucleotide-binding homology domain of the hERG channel
1UJL 2003-11-04 Solution Structure of the HERG K+ channel S5-P extracellular linker
2L4R 2010-12-22 NMR solution structure of the N-terminal PAS domain of hERG
2LE7 2012-04-25 Solution nmr structure of the S4S5 linker of herg potassium channel
2L0W 2011-01-26 Solution NMR structure of the N-terminal PAS domain of HERG potassium channel
2L1M 2011-01-19 Solution structure of the eag domain of the hERG (Kv11.1) K+ channel
4HQA 2013-03-27 1.96 Crystal structure of PAS domain from the human ERG (hERG) potassium channel
4HP9 2013-03-27 2.12 Crystal structure of the N-terminal truncated PAS domain from the hERG potassium channel
1BYW 1998-12-16 2.6 STRUCTURE OF THE N-TERMINAL DOMAIN OF THE HUMAN-ERG POTASSIUM CHANNEL
5VA1 2017-05-03 3.7 Cryo-EM structure of the human ether-a-go-go related K+ channel
5VA2 2017-05-03 3.8 Cryo-EM structure of the human ether-a-go-go related K+ channel
5VA3 2017-05-03 4.0 Cryo-EM structure of the human ether-a-go-go related K+ channel

Relevant UniProtKB Entries

Percent Identity Matching Chains Protein Accession Entry Name
99.1 Potassium voltage-gated channel subfamily H member 2 O08962 KCNH2_RAT
99.1 Potassium voltage-gated channel subfamily H member 2 Q8WNY2 KCNH2_RABIT
99.1 Potassium voltage-gated channel subfamily H member 2 O35219 KCNH2_MOUSE
99.1 Potassium voltage-gated channel subfamily H member 2 Q12809 KCNH2_HUMAN
99.1 Potassium voltage-gated channel subfamily H member 2 Q9TSZ3 KCNH2_CANLF