Structure of full-length human TRPM4

Area of Science:

• Structural biology
• Ion channel biophysics
• Cardiovascular research

Background:

• Transient receptor potential melastatin subfamily member 4 (TRPM4) is a calcium-activated, monovalent-selective cation channel.
• Mutations in human TRPM4 (hTRPM4) are linked to progressive familial heart block, highlighting its critical role in cardiac function.

Purpose of the Study:

• To determine the high-resolution structure of human TRPM4 in a closed state.
• To elucidate the gating mechanisms and regulatory interactions of hTRPM4.

Main Methods:

• Electron cryomicroscopy (cryo-EM) was used to resolve the structure of hTRPM4.
• The structure was determined at a resolution of 3.7 Å in a closed, Na+-bound, apo state at pH 7.5.

Main Results:

• The structure reveals an upper gate in the selectivity filter and a lower gate at the cytoplasmic coiled-coil domain entrance.
• Five sodium ions are localized within the pore and at the coiled-coil domain entrance.
• Identified intramolecular interactions, aromatic interactions (π-π, cation-π), extracellular glycosylation, a pore-loop disulfide bond, and lipid binding sites.

Conclusions:

• The determined hTRPM4 structure provides a molecular basis for understanding its gating and regulation.
• Insights into TRPM4 structure can inform the study of channelopathies like familial heart block.
• This work offers a foundation for future investigations into TRPM4 function and modulation.