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Constructing ion channels from water-soluble α-helical barrels

DOI: 10.1038/s41557-021-00688-0 DOI Help

Authors: Alistair J. Scott (University of Bristol) , Ai Niitsu (University of Bristol) , Huong T. Kratochvil (University of California San Francisco) , Eric J. M. Lang (University of Bristol) , Jason T. Sengel (King’s College London) , William M. Dawson (University of Bristol) , Kozhinjampara R. Mahendran (University of Oxford) , Marco Mravic (University of California San Francisco) , Andrew Thomson (University of Bristol) , R. Leo Brady (University of Bristol) , Lijun Liu (Peking University Shenzhen Graduate School) , Adrian J. Mulholland (University of Bristol) , Hagan Bayley (University of Oxford) , William F. Degrado (University of California San Francisco) , Mark I. Wallace (King’s College London) , Derek N. Woolfson (University of Bristol)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Chemistry , VOL 537

State: Published (Approved)
Published: May 2021

Abstract: The design of peptides that assemble in membranes to form functional ion channels is challenging. Specifically, hydrophobic interactions must be designed between the peptides and at the peptide–lipid interfaces simultaneously. Here, we take a multi-step approach towards this problem. First, we use rational de novo design to generate water-soluble α-helical barrels with polar interiors, and confirm their structures using high-resolution X-ray crystallography. These α-helical barrels have water-filled lumens like those of transmembrane channels. Next, we modify the sequences to facilitate their insertion into lipid bilayers. Single-channel electrical recordings and fluorescent imaging of the peptides in membranes show monodisperse, cation-selective channels of unitary conductance. Surprisingly, however, an X-ray structure solved from the lipidic cubic phase for one peptide reveals an alternative state with tightly packed helices and a constricted channel. To reconcile these observations, we perform computational analyses to compare the properties of possible different states of the peptide.

Journal Keywords: Ion channels; Peptides

Subject Areas: Chemistry, Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Discipline Tags:

Organic Chemistry Life Sciences & Biotech Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)