A two-domain elevator mechanism for sodium/proton antiport

Area of Science:

• Structural Biology
• Biochemistry
• Membrane Transport

Background:

• Sodium/proton (Na+/H+) antiporters are crucial for cellular homeostasis and are implicated in human diseases.
• The NhaA antiporter from E. coli is a well-studied model, but its structure represents an inactive state.
• Understanding the active conformation of these transporters is key to developing new therapeutics.

Purpose of the Study:

• To determine the active-state structure of a Na+/H+ antiporter.
• To elucidate the mechanism of ion transport in Na+/H+ antiporters.
• To provide insights into the general transport mechanism of secondary-active transporters.

Main Methods:

• X-ray crystallography at 3 Å resolution
• Molecular dynamics simulations
• Biochemical assays (implied by functional context)

Main Results:

• The active-state structure of Thermus thermophilus NapA was solved at pH 7.8.
• NapA exhibits a distinct domain arrangement compared to NhaA, with an extracellular cavity.
• A conserved aspartate residue is positioned for ion coordination, accessed via a large core domain rotation (~20°).

Conclusions:

• Na+/H+ antiporters operate via a two-domain rocking bundle mechanism.
• This mechanism involves significant domain rotation to alternate access to the ion-binding site.
• The findings offer generalizable insights into the function of secondary-active transporters.