Four Intrinsic Aqueduct Orifices Outstretched from the Central Cavity Facilitate Potassium Channels Gating

Abstract

Potassium channels enable K+ ions to flow selectively across cell membrane through a central pore. The mechanisms of ion selectivity and channel gating have long been the attractive secrets. The breakthrough in determination of the structure of the KcsA potassium channel (Science 280, 69-77, 1998) has raised a high tide in structure and function study, but channel gating still remains a long secret. The core structure of K+ channels was found to be highly conserved, and constructed of an inverted teepee with a large water-filled cavity at center and the well studied selectivity filter at its wide end. Here we find four aqueduct orifices outstretched from the cavity and perpendicular to the central pore, leading to shape of a swastika or Greek Fleuree Cross, having subtle gating function. We demonstrated by systematical molecular dynamics simulations that water molecules flowing in the orifices can harmonize the space changing in the cavity to reduce the opening resistance significantly, and blocking the aqueduct orifices makes the intracellular entryway difficult to be opened. This is strongly supported by existed mutation experiments. Homology analyses of all available pore structures and amino acid sequences of K+ channels show that the aqueduct orifices are intrinsic structure feature to the whole potassium channel genre, but their size and conformation are less conserved among different subfamilies, shedding light on their functional diversity.Potassium and water channels have been the wining channels for 2003 Nobel prize. The finding of the intrinsic aqueduct orifices and their vital functions in channel gating shows water flowing merges with ion activity. The orifices even exist in the newly determined atomic structure of NaK channel (Nature 440, 570-574, 2006), which belongs to another large ion channel family (cyclic nucleotide-gated channels).