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Ion channel structure and function of the MERS coronavirus E protein
Iva Sučec1, Bingqing Xia2, Noah H Somberg1
1Department of Chemistry, Massachusetts Institute of Technology, 170 Albany Street, Cambridge, MA 02139, USA.
Abstract:
Coronavirus envelope (E) proteins form drug-targeted ion channels that cause virulence to infected cells. The Middle East respiratory syndrome (MERS) virus has high mortality rates, but its E structure and function are unknown. We report the single-channel conductance and structure of membrane-bound MERS E protein. MERS E conducts K+ ions with a unitary conductance of 113 picosiemens, fivefold larger than the conductance of severe acute respiratory syndrome coronavirus 2 E. Solid-state nuclear magnetic resonance data indicate that the MERS E transmembrane domain forms a five-helix bundle that spans the lipid bilayer. The amino-terminal helical interface features multiple interacting phenylalanine (Phe) residues and an asparagine (Asn), whereas the carboxyl-terminal channel pore contains Phe33. Mutation of Phe17 abolished K+ conductance, whereas mutations of Phe33 and Asn15 suppressed most channel activity. These results indicate that MERS E contains two Phe-centered ion-conduction apparatuses, which likely permeate ions through cation-π interactions, providing the structural basis for developing antiviral drugs to inhibit this pathogenic viroporin.
Insights
The Middle East respiratory syndrome (MERS) virus envelope (E) protein forms an ion channel. This channel
Area of Science:
- Structural Biology
- Virology
- Biophysics
Background:
- The Middle East respiratory syndrome (MERS) virus exhibits high mortality rates.
- The structure and function of the MERS virus envelope (E) protein, a key component in viral virulence, remain largely unknown.
- Coronavirus E proteins are known to form ion channels targeted by antiviral drugs.
Purpose of the Study:
- To determine the structure and function of the membrane-bound MERS virus E protein.
- To investigate the ion conduction properties and structural basis of the MERS E protein.
Main Methods:
- Solid-state nuclear magnetic resonance (ssNMR) spectroscopy was employed to determine the protein structure.
- Single-channel electrophysiology was used to measure ion conductance.
- Site-directed mutagenesis was performed to identify key residues for channel function.
Main Results:
- The MERS E protein forms a five-helix bundle spanning the lipid bilayer.
- MERS E conducts potassium (K+) ions with a unitary conductance of 113 picosiemens, significantly higher than SARS-CoV-2 E.
- Key residues, including phenylalanine (Phe) at positions 17 and 33, and asparagine (Asn) at position 15, are critical for ion conductance.
- Two Phe-centered ion-conduction pathways were identified, likely utilizing cation-π interactions.
Conclusions:
- The MERS E protein functions as a K+ selective ion channel with a unique structural architecture.
- The identified structural features provide a basis for the rational design of MERS-specific antiviral therapies targeting the E protein viroporin.
- Understanding the MERS E protein's ion channel activity is crucial for combating MERS-CoV infections.
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