Characterization of an LQT5-related mutation in KCNE1, Y81C: Implications for a role of KCNE1 cytoplasmic domain in IKs channel function

Wu, Dongmei; Lai, Ling‐Ping; Zhang, Mei; Wang, Hui-Liang; Jiang, Min; Liu, Xiansheng; Tseng, Gea‐Ny

doi:10.1016/j.hrthm.2006.05.022

Cited by 18 publications

(7 citation statements)

References 36 publications

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“…These I Ks activators work from outside the cell membrane by shifting the voltage dependence of Q1 activation in the negative direction. The degree of shift is enhanced by E1 association ( Wu et al, 2006b ). Mutations or deletions in the 39 -42 region of E1 abolish these activators ' actions ( Abitbol et al, 1999 ).…”

Section: Introductionmentioning

confidence: 99%

KCNQ1 and KCNE1 in the IKs Channel Complex Make State-dependent Contacts in their Extracellular Domains

Jiang

Hsu

et al. 2008

The Journal of General Physiology

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125

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KCNQ1 and KCNE1 (Q1 and E1) associate to form the slow delayed rectifi er I Ks channels in the heart. A short stretch of eight amino acids at the extracellular end of S1 in Q1 (positions 140 -147) harbors six arrhythmia-associated mutations. Some of these mutations affect the Q1 channel function only when coexpressed with E1, suggesting that this Q1 region may engage in the interaction with E1 critical for the I Ks channel function. Identifying the Q1/E1 contact points here may provide new insights into how the I Ks channel operates. We focus on Q1 position 145 and E1 positions 40 -43. Replacing all native cysteine (Cys) in Q1 and introducing Cys into the above Q1 and E1 positions do not signifi cantly perturb the Q1 channel function or Q1/E1 interactions. Immunoblot experiments on COS-7 cells reveal that Q1 145C can form disulfi de bonds with E1 40C and 41C, but not E1 42C or 43C. Correspondingly, voltage clamp experiments in oocytes reveal that Q1 145C coexpressed with E1 40C or E1 41C manifests unique gating behavior and DTT sensitivity. Our data suggest that E1 40C and 41C come close to Q1 145C in the activated and resting states, respectively, to allow disulfi de bond formation. These data and those in the literature lead us to propose a structural model for the Q1/E1 channel complex, in which E1 is located between S1, S4, and S6 of three separate Q1 subunits. We propose that E1 is not a passive partner of the Q1 channel, but instead can engage in molecular motions during I Ks gating.on May 7, 2018 jgp.rupress.org Downloaded from

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Section: Introductionmentioning

confidence: 99%

KCNQ1 and KCNE1 in the IKs Channel Complex Make State-dependent Contacts in their Extracellular Domains

Jiang

Hsu

et al. 2008

The Journal of General Physiology

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125

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“…E1 makes extensive contacts with Q1, including the transmembrane region (Melman et al 2001; Panaghie et al 2006; Tai and Goldstein 1998; Tapper and George 2001), the cytoplasmic region (Haitin et al 2009; Lvov et al 2010; Wiener et al 2008), and the extracellular region (Chung et al 2009; Nakajo and Kubo 2007; Xu et al 2008). Q1/E1 interactions in the transmembrane region determine the I Ks pore conductance (Sesti and Goldstein 1998; Yang and Sigworth 1998) and gating kinetics (Melman et al 2001), while Q1/E1 interactions in the cytoplasmic region influence I Ks trafficking (Ghosh et al 2006; Shamgar et al 2006), modulation by protein kinase A-mediated phosphorylation (Kurokawa et al 2009), and gating kinetics (Lvov et al 2010; Wu et al 2006). However, the functional roles of Q1/E1 interactions in the extracellular region are not clear.…”

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confidence: 99%

Gating-Related Molecular Motions in the Extracellular Domain of the IKs Channel: Implications for IKs Channelopathy

Wang

Jiang

et al. 2010

J Membrane Biol

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Cardiac slow delayed rectifier (IKs) channel complex consists of KCNQ1 channel and KCNE1 auxiliary subunits. The extracellular juxtamembranous region of KCNE1 is an unstructured loop that contacts multiple KCNQ1 positions in a gating-state-dependent manner. Congenital arrhythmia-related mutations have been identified in the extracellular S1–S2 linker of KCNQ1. These mutations manifest abnormal phenotypes only when coexpressed with KCNE1, pointing to the importance of proper KCNQ1/KCNE1 interactions here in IKs channel function. We investigate the interactions between the KCNE1 loop (positions 36–47) and KCNQ1 S1–S2 linker (positions 140–148) by means of disulfide trapping and voltage clamp techniques. During transitions among the resting-state conformations, KCNE1 positions 36–43 make contacts with KCNQ1 positions 144, 145, and 147 in a parallel fashion. During conformational changes in the activated state, KCNE1 position 40 can make contacts with all three KCNQ1 positions, while the neighboring KCNE1 positions (36, 38, 39, and 41) can make contact with KCNQ1 position 147. Furthermore, KCNQ1 positions 143 and 146 are high-impact positions that cannot tolerate cysteine substitution. To maintain the proper IKs channel function, position 143 requires a small side chain with a hydroxyl group, and position 146 requires a negatively charged side chain. These data and the proposed molecular motions provide insights into the mechanisms by which mutations in the extracellular juxtamembranous region of the IKs channel impair its function.

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“…Interestingly, KCNE1, CACNA1C, and KCNQ2 are already targets of drugs against arrhythmia, atrial fibrillation, congestive heart failure, left ventricular hypertrophy, and isolated systolic hypertension (42). Furthermore, there is recent evidence that the post-transmembrane domain region of KCNE1 interacts with the KCNQ1 channel to modulate the I(K) current amplitude and gating kinetics (43).…”

Section: Resultsmentioning

confidence: 99%

From Single Variants to Protein Cascades

Mueller

Sommer

Backes

et al. 2016

Journal of Biological Chemistry

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Understanding the role of genetics in disease has become a central part of medical research. Non-synonymous single nucleotide variants (nsSNVs) in coding regions of human genes frequently lead to pathological phenotypes. Beyond single variations, the individual combination of nsSNVs may add to pathogenic processes. We developed a multiscale pipeline to systematically analyze the existence of quantitative effects of multiple nsSNVs and gene combinations in single individuals on pathogenicity. Based on this pipeline, we detected in a data set of 842 nsSNVs discovered in 76 genes related to cardiomyopathies, associated nsSNV combinations in seven genes present in at least 70% of all 639 patient samples, but not in a control cohort of healthy humans. Structural analyses of these revealed primarily an influence on the protein stability. For amino acid substitutions located at the protein surface, we generally observed a proximity to putative binding pockets. To computationally analyze cumulative effects and their impact, pathogenicity methods are currently being developed. Our approach supports this process, as shown on the example of a cardiac phenotype but can be likewise applied to other diseases such as cancer.

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Characterization of an LQT5-related mutation in KCNE1, Y81C: Implications for a role of KCNE1 cytoplasmic domain in IKs channel function

Cited by 18 publications

References 36 publications

KCNQ1 and KCNE1 in the IKs Channel Complex Make State-dependent Contacts in their Extracellular Domains

KCNQ1 and KCNE1 in the IKs Channel Complex Make State-dependent Contacts in their Extracellular Domains

Gating-Related Molecular Motions in the Extracellular Domain of the IKs Channel: Implications for IKs Channelopathy

From Single Variants to Protein Cascades

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