Dynamic conformational changes of extracellular S5–P linkers in the hERG channel

• Published in: The Journal of physiology Vol. 569; no. 1; pp. 75 - 89
• Main Authors: Jiang, Min, Zhang, Mei, Maslennikov, Innokenty V., Liu, Jie, Wu, Dong‐Mei, Korolkova, Yuliya V., Arseniev, Alexander S., Grishin, Eugene V., Tseng, Gea‐Ny
• Format: Journal Article
• Language: English
• Published: 9600 Garsington Road , Oxford , OX4 2DQ , UK Blackwell Science Ltd 15.11.2005; Blackwell Science Inc
• Subjects: Amino Acid Sequence; Binding Sites; Computer Simulation; Ether-A-Go-Go Potassium Channels - analysis; Ether-A-Go-Go Potassium Channels - chemistry; Extracellular Space - chemistry; Models, Chemical; Models, Molecular; Molecular and Genomic Physiology; Molecular Sequence Data; Protein Binding; Protein Conformation; Protein Subunits; Structure-Activity Relationship
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/jphysiol.2005.093682

The hERG channel has an unusually long ‘S5–P linker’ (residues 571–613) that lines the outer mouth of the pore. Previously, we have shown that residues along this S5–P linker are critical for the fast‐inactivation process and K+ selectivity of the hERG channel. Here we used several approaches to probe the structure of this S5–P linker and its interactions with other domains of the hERG channel. Circular dichroism and NMR analysis of a synthetic hERG S5–P linker peptide suggested that this linker is quite dynamic: its central region (positions 583–593) can be unstructured or helical, depending on whether it is immersed in an aqueous phase or in contact with a hydrophobic environment. Cysteine introduced into positions 583–597 of the S5–P linker can form intersubunit disulphide bonds, and at least four of them (at 584, 585, 588 and 589) can form disulphide bonds with counterparts from neighbouring subunits. We propose that the four S5–P linkers in a hERG channel can engage in dynamic conformational changes during channel gating, and interactions between S5–P linkers from neighbouring subunits contribute importantly to channel inactivation.