Editorial: Structural and functional roles of membrane transport proteins in cellular physiology

Membrane pores, channels, and transporters govern the passage of ions and molecules across biological membranes and sit at the heart of cellular physiology. Despite major advances from cryo-electron microscopy, NMR, and molecular dynamics simulations, the dynamics of these proteins and their interactions within diverse biological contexts remain incompletely understood.

This Research Topic set out to synthesize recent progress and address open questions on the molecular mechanisms of membrane transport. The five contributions span multiple scales and systems - bacterial expression platforms, archaeal lipid adaptation, neuronal metal-ion signaling, disorder-based regulation, and plant nitrate flux - yet share a common thread: how the structure, dynamics, and environment of transport machinery dictate function. We would like to mention though that most of the collection is not based on the original research but rather presents reviews and opinions.

Two papers approach transport from the protein and membrane side. Tabefam et al., present a robust, cost-effective strategy for expressing, purifying, and reconstituting mitochondrial carrier family proteins—UCP4, adenine nucleotide translocase (ANT), and phosphate translocase (PiT) — in native-like conformations. By adding an N-terminal pelB leader and a His-tag, the authors directed recombinant proteins to the E. coli inner membrane, avoiding inclusion bodies and the need for refolding. Optimized autoinduction across multiple strains yielded high quantities of membrane-embedded protein, purified by immobilized metal affinity chromatography, with native α-helical content confirmed by circular dichroism. Reconstituted into liposomes mimicking the mitochondrial inner membrane, UCP4 spontaneously assembled into stable tetramers while ANT and PiT remained monomeric—a protein-specific difference in oligomerization that this platform is well suited to probe. Complementing this, Chong, reviews how the membranes of thermoacidophilic archaea withstand extreme acidity (pH ≤ 4) and heat (≥65 °C) through the unique properties of bipolar tetraether lipids such as GDNT and GDGT. Environmental pH drives systematic compositional tuning—cyclopentane ring number, GDNT/GDGT ratio, tetraether-to-diether balance, and headgroup glycosylation—that reshapes hydrogen-bonding networks, packing density, and rigidity. These adjustments minimize volume fluctuations and keep passive proton permeability extremely low, allowing archaea to maintain near-neutral internal pH and preserve protein activity under conditions that would otherwise be lethal.

Two further reviews turn to the regulation of transport activity. Sabouri et al., examine zinc (Zn²⁺) homeostasis in the brain, controlled largely by the ZnT (SLC30) and ZIP (SLC39) transporter families that respectively lower and raise cytosolic zinc. Beyond its structural and catalytic roles, Zn²⁺ acts as a dynamic signaling molecule that modulates ion channels and receptors, shaping synaptic transmission. The authors link dysregulated transport to neurodegenerative disease, including Alzheimer’s, and survey therapeutic strategies aimed at restoring zinc balance. Vinogradova, then challenges the classical “one structure–one function” paradigm, showing how intrinsically disordered proteins and regions (IDPs/IDRs) regulate ion channels and transporters as dynamic conformational ensembles. IDRs contribute to gating, ligand recognition, protein–protein interactions, and allosteric control; capturing their behavior demands integrative approaches, particularly solution NMR combined with molecular dynamics, and their dysfunction carries clear disease implications.

Finally, Le Deunff and Malagoli offer a hypothesis and theory contribution that reexamines nitrate uptake in plants. Analyzing ¹⁵N flux data, they argue for nonlinear, state-dependent transitions rather than continuous enzyme-like kinetics, challenging the classical interpretation of Epstein’s biphasic isotherms. Their three-compartment soil–root–shoot model attributes threshold-like regime shifts to changes in radial and longitudinal transport resistance, with repeated root units behaving like biological varistors. The framework aligns with the behavior of NRT1.1/NPF6.3-like systems and invokes NRT2.1 and Ca²⁺-dependent CBL–CIPK signaling, with practical implications for nitrogen use efficiency in crops.

Together, these contributions illustrate that membrane transport cannot be understood from static structure alone: lipid environment, conformational disorder, oligomeric state, and system-level organization all shape function. We want to emphasize the importance of integrative studies (including electrophysiology, calorimetry, FRET, LRET, etc.) to complement and correct, when necessary, mis concepts that might be originated from structural studies alone. We hope this collection serves as a continually updated resource and a stimulus for the integrative, multi-scale studies the field now needs. We thank all authors for their contributions and the reviewers for their careful evaluation.

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Footnotes

Edited by: Joao L. Carvalho-de-Souza, Midwestern University, United States

Reviewed by: Carlos Bassetto, University of Texas at San Antonio, United States

Claudio Grosman, University of Illinois at Urbana-Champaign, United States

Maria Zoghbi, University of California, Merced, United States