Working model for the structural basis for KCNE1 modulation of the KCNQ1 potassium channel

Abstract

The voltage-gated potassium channel KCNQ1 (Kv7.1) is modulated by KCNE1 (minK) to generate the I(Ks) current crucial to heartbeat. Defects in either protein result in serious cardiac arrhythmias. Recently developed structural models of the open and closed state KCNQ1/KCNE1 complexes offer a compelling explanation for how KCNE1 slows channel opening and provides a platform from which to refine and test hypotheses for other aspects of KCNE1 modulation. These working models were developed using an integrative approach based on results from nuclear magnetic resonance spectroscopy, electrophysiology, biochemistry, and computational methods-an approach that can be applied iteratively for model testing and revision. We present a critical review of these structural models, illustrating the strengths and challenges of the integrative approach.

Figure 1. Voltage-gated potassium ion channel and KCNE protein topology and structural model of KCNQ1

A) KCNQ1 is a 6TM voltage-gated channel that has two membrane integral domains, the voltage-sensor domain (blue, S1–S4) and the pore domain (green, S5–S6). A schematic representation of KCNE1 is shown as a red cylinder that represents the single transmembrane helix common to all KCNE family members. B) Homology models illustrate the tetrameric nature of KCNQ1. Protein Databank-format coordinates for the open and closed states models of KCNQ1 are originally from Smith et al. [48] and can be found in the on-line supplementary information.

Figure 2. Electrophysiology recordings detailing KCNE modulation of KCNQ1

Whole-cell currents elicited from CHO cells transiently expressing KCNQ1 alone or with KCNE proteins (Vanoye et al, unpublished data). A) Current profile of KCNQ1 in the absence of any KCNE protein. B) Effects of KCNE1 modulation of KCNQ1 activity: slower channel activation and increased current density. C) KCNE3 alters the KCNQ1 properties to make channel activation nearly instantaneous and voltage-independent, as well as to increase current density. E) KCNE4 is a strict inhibitor of KCNQ1. E) and F) show the current and time scales for the recorded data and the voltage protocol used, respectively.

Figure 3. Integrative approach to developing structural models

Various types of data obtained by electrophysiology, biochemistry, and biophysical approaches are used in conjunction with experimental and computational structural data to generate hybrid structural models. An important feature of this is that the model accuracy can be cross-validated by new functional studies and iteratively updated as new data and/or improved restrained modeling methods become available.

Figure 4. Structural models of the KCNQ1/KCNE1-TMD open and closed state complexes

A) and B) illustrate representative structures from the data-allowable ensembles of structures for the closed and open states model complex where KCNE1 strategically binds to proximal clefts in KCNQ1[33]. According to the structural models, KCNE1 undergoes a modest micro-dissociation/re-association from one cleft to another that is accompanied by partial rotation. However, KCNQ1 undergoes a relatively major conformation change between states. Protein Databank-format coordinates and videos illustrating the conversion between states were published by Kang et al. [33] and are available in the supplementary information of this review. C) through F) feature shaded residues in KCNQ1 for which Cα are within 10 Å of a Cα from at least one residue in the KCNE1-TMD.