Structure of the Cyclic Nucleotide-Binding Homology Domain of the hERG Channel and Its Insight into Type 2 Long QT Syndrome.

Yan Li,Hui Qi Ng,Qingxin Li,Congbao Kang

doi:10.1038/srep23712

Abstract

The human ether-à-go-go related gene (hERG) channel is crucial for the cardiac action potential by contributing to the fast delayed-rectifier potassium current. Mutations in the hERG channel result in type 2 long QT syndrome (LQT2). The hERG channel contains a cyclic nucleotide-binding homology domain (CNBHD) and this domain is required for the channel gating though molecular interactions with the eag domain. Here we present solution structure of the CNBHD of the hERG channel. The structural study reveals that the CNBHD adopts a similar fold to other KCNH channels. It is self-liganded and it contains a short β-strand that blocks the nucleotide-binding pocket in the β-roll. Folding of LQT2-related mutations in this domain was shown to be affected by point mutation. Mutations in this domain can cause protein aggregation in E. coli cells or induce conformational changes. One mutant-R752W showed obvious chemical shift perturbation compared with the wild-type, but it still binds to the eag domain. The helix region from the N-terminal cap domain of the hERG channel showed unspecific interactions with the CNBHD.

Highlights

KCNH channels are voltage-gated potassium channels whose function is regulated by changes in the membrane potential[9]
The solution structure of human ether-à-go-go related gene (hERG) cyclic nucleotide-binding homology domain (CNBHD) was solved using restraints including NOEs derived from a 15N- and a 13C-edited NOESY experiments, dihedral angles obtained from TALOS+ 30, and hydrogen bond restraints derived from an H-D exchange experiment (Fig. 1B, and Table 1)
We showed that the structure of the CNBHD of the hERG channel does not favor the interactions with cyclic nucleotide (Fig. 1), which is confirmed by the NMR experiment (Fig. 1)

Summary

Introduction

KCNH channels are voltage-gated potassium channels whose function is regulated by changes in the membrane potential[9]. We show that mutations in CNBHD of hERG channel could cause conformational changes that can affect protein stability. The calculated structure reveals that the CNBHD of the hERG channel contains 9 β -strands and 3 helices (Fig. 1B,C).

Results

Conclusion