Dynamic landscape of the intracellular termini of acid-sensing ion channel 1a

Author:

Cullinan Megan M1ORCID,Klipp Robert C1,Camenisch Abigail2,Bankston John R1ORCID

Affiliation:

1. Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus

2. University of Arizona College of Medicine

Abstract

Acid-sensing ion channels (ASICs) are trimeric proton-gated sodium channels. Recent work has shown that these channels play a role in necroptosis following prolonged acidic exposure like occurs in stroke. The C-terminus of ASIC1a is thought to mediate necroptotic cell death through interaction with receptor interacting serine threonine kinase 1 (RIPK1). This interaction is hypothesized to be inhibited at rest via an interaction between the C- and N-termini which blocks the RIPK1 binding site. Here, we use two transition metal ion FRET methods to investigate the conformational dynamics of the termini at neutral and acidic pH. We do not find evidence that the termini are close enough to be bound while the channel is at rest and find that the termini may modestly move closer together during acidification. At rest, the N-terminus adopts a conformation parallel to the membrane about 10 Å away. The distal end of the C-terminus may also spend time close to the membrane at rest. After acidification, the proximal portion of the N-terminus moves marginally closer to the membrane whereas the distal portion of the C-terminus swings away from the membrane. Together these data suggest that a new hypothesis for RIPK1 binding during stroke is needed.

Funder

National Institute of General Medical Sciences

National Eye Institute

National Institute of Dental and Craniofacial Research

National Heart, Lung, and Blood Institute

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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