A different mechanism of C-type inactivation in the Kv-like KcsA mutant E71V

• DOI: 10.1101/2021.09.22.461404
• Publication Date: 2021-09-23T05:52:11Z
• Authors: Ahmed Rohaim; Bram J.A. Vermeulen; Jing Li; Felix Kümmerer; Federico Napoli; Lydia Blachowicz; João Medeiros-Silva; Benoit Roux; Markus Weingarth
• Keywords: KcsA potassium channel; Helix (gastropod)

ABSTRACT A large class of K + channels display a time-dependent phenomenon called C-type inactivation whereby prolonged activation by an external stimulus leads to non-conductive conformation the selectivity filter. is great physiological importance particularly in voltage-activated (Kv), affecting firing patterns neurons and shaping cardiac action potentials. While understanding molecular basis has direct impact on human health, its structural remains unresolved. Knowledge about been largely deduced from pH-activated bacterial channel KcsA, whose filter under inactivating conditions adopts constricted at level central glycine (TTV G YGD) that stabilized tightly bound water molecules. However, highly sensitive environment surrounding pore domain, which different Kv than model KcsA. In particular, glutamic acid residue position 71 along helix KcsA consistently substituted nonpolar valine most channels, suggesting this side chain important determinant function. Here, combination X-ray crystallography, solid-state NMR dynamics simulations E71V mutant undertaken explore features associated with Kv-like construct. both ssNMR data, it observed does not adopt familiar conditions. Rather, appears slightly narrowed rigidified over entire length. No molecules are present. On other hand, indicate can nonetheless be stably established channel. Together, these findings suggest mutation may modes inactivation, showing distinct environments entail mechanisms.