1497-Structural Principles of CNNM4 Magnesium Transport

The paper describe the discovery of a unique tetrameric structure in the human CNNM4 protein, a vital regulator of magnesium levels in the body. Unlike its bacterial relatives that form simple pairs, human CNNM4 assembles as a dimer of dimers, a complex architecture stabilized by the binding of MgATP. Researchers utilized cryoelectron microscopy to capture the transporter in distinct "outward-facing" and "occluded" states, revealing how the protein transitions to move ions across the cell membrane. A key finding is the identification of an intracellular acidic patch that acts as a sensor, allowing the protein to detect and respond to internal magnesium concentrations. Additionally, the study explains how a specific glutamate residue facilitates the exchange of sodium and magnesium, providing a mechanical framework for understanding human magnesium homeostasis. These insights are medically significant, as they link specific structural defects in CNNM4 to genetic conditions like Jalili syndrome and other physiological disorders.

References:

• Bai Z, Zhou X E, Lü W, et al. Dynamic dimer-of-dimers architecture defines Mg2+ transport in human CNNM4[J]. Cell, 2026.