Inherent Dynamics of the Acid-Sensing Ion Channel 1 Correlates with the Gating Mechanism

Huaiyu Yang, Ye Yu, Wei-Guang Li, Fang Yu, Hui Cao, Tian-Le Xu, Hualiang Jiang

Abstract

The acid-sensing ion channel 1 (ASIC1) is a key receptor for extracellular protons. Although numerous structural and
functional studies have been performed on this channel, the structural dynamics underlying the gating mechanism remains
unknown. We used normal mode analysis, mutagenesis, and electrophysiological methods to explore the relationship
between the inherent dynamics of ASIC1 and its gating mechanism. Here we show that a series of collective motions among
the domains and subdomains of ASIC1 correlate with its acid-sensing function. The normal mode analysis result reveals that
the intrinsic rotation of the extracellular domain and the collective motions between the thumb and finger induced by
proton binding drive the receptor to experience a deformation from the extracellular domain to the transmembrane
domain, triggering the channel pore to undergo ‘‘twist-to-open’’ motions. The movements in the transmembrane domain
indicate that the likely position of the channel gate is around Leu440. These motion modes are compatible with a wide
body of our complementary mutations and electrophysiological data. This study provides the dynamic fundamentals of
ASIC1 gating.