Traditionally, it was postulated that amino acids exert their protective influence on proteins through biological means, specifically by preventing misfolding via interactions tailored to biological systems. However, this recent study overturns that assumption. The research elucidates that the stabilizing role of amino acids transcends biological specificity and instead emerges from fundamental physical chemistry principles that govern colloidal interactions. These findings pivotally shift the paradigm by revealing that all small molecules in solution possess intrinsic colloidal effects that modulate the interactions of larger particles such as proteins.

The team’s approach involved dissecting the complex interplay between proteins and amino acids by examining the solution environment as a dynamic system of particles of varying sizes and interaction potentials. Central to their discoveries is the concept of “screening attraction,” a phenomenon where small molecules diminish the effective attractive forces between larger particles in solution. To visualize this, Francesco Stellacci, head of the laboratory, offers an analogy involving two colleagues walking towards each other in a hallway: in an empty corridor, the two easily spot one another and engage, but a crowded hallway prevents their interaction. Here, amino acids act as the metaphorical crowd, physically impeding the closeness between proteins.

This principle of screening attraction is complementary to a known, yet contrasting effect attributed to salts, which have historically been understood to “screen repulsion.” Salts, through their charged ions, shield repulsive electrostatic forces between similarly charged protein surfaces, facilitating proximity and interaction. However, amino acids inversely mitigate attractive forces, a discovery that sheds light on why these small molecules are exceptional stabilizers. This “anti-salt” behavior means amino acids contribute to maintaining the dispersion of proteins by effectively reducing their propensity to clump or aggregate.

The implications of this discovery extend deeply into biological systems. For example, it has been observed in plant biology that exposure to saline environments triggers an increased biosynthesis of amino acids, presumably as a protective response to the destabilizing influence of salt on cellular proteins. Understanding this molecular mechanism offers profound insights into stress responses at the cellular level and reveals previously unappreciated strategies that organisms employ to preserve protein function under adverse environmental conditions.

From a practical standpoint, this work urges a re-evaluation of experimental protocols in biomedical research and industrial formulations. It advocates for meticulous reporting of amino acid concentrations, akin to the already-standard practice of reporting ionic strengths in solution chemistry. Overlooking the concentration and identity of stabilizing small molecules in experimental setups may obscure reproducibility and the interpretation of biochemical phenomena, especially in protein therapeutics development where stability is paramount.

The study’s pioneering perspective also opens avenues for predictive design in protein stabilization. Leveraging the newfound understanding of small molecule-colloid interactions, researchers, including Stellacci himself through his ERC Advanced Grant, aim to develop computational and experimental tools to forecast which small molecules can optimally stabilize specific proteins. Such predictive capabilities would drastically reduce the current dependency on time-consuming trial-and-error methods, accelerating the formulation of stable biopharmaceutical products, enhancing drug efficacy, and reducing production costs.

Technically, this research sits at the intersection of colloid science, physical chemistry, and biophysics. The experimental methodologies applied involved precision measurements of macromolecular interactions modulated by varying concentrations and species of small molecules in solution. The findings underscore the significance of entropic and enthalpic contributions mediated by the spatial distribution of amino acids around proteins, influencing the net interaction potentials that govern colloidal stability.

This study’s publication in Nature marks a milestone in molecular science, bridging fundamental colloidal theory with practical biological and pharmaceutical applications. It also illustrates the power of international collaboration spanning institutions such as EPFL, MIT, and the Southern University of Science and Technology in China, uniting expertise to unravel complex biochemical puzzles that have persisted through decades of investigation.

In conclusion, the revelation that amino acids function as colloidal “screens” reframes our understanding of protein stabilization literally at the molecular level. By balancing the forces of attraction and repulsion through these small molecules, cells—and by extension, medical formulations—may finely tune protein behavior, preventing aggregation and misfolding. This discovery not only holds promise for enhancing drug stability but also provides a conceptual scaffold for exploring how cellular environments can be engineered or modulated to maintain protein homeostasis.

As research progresses, the scientific community anticipates further exploration into the nuanced roles of small molecules in colloidal systems and their broader impact across life sciences and materials chemistry. This paradigm shift underscores the subtle yet profound ways in which molecular-scale interactions dictate biological function, informing both fundamental science and translational medicine for years to come.

Subject of Research: Stabilizing effect of amino acids on protein and colloidal dispersions

Article Title: Stabilizing effect of amino acids on protein and colloidal dispersions

News Publication Date: 10-Sep-2025

Web References:
https://www.nature.com/articles/s41586-025-09506-w

References:
Mao, T., Alexander-Katz, A., Luo, Z., Ong, Q., Stellacci, F., et al. (2025). Stabilizing effect of amino acids on protein and colloidal dispersions. Nature. DOI: 10.1038/s41586-025-09506-w

Image Credits:
2025 SuNMIL EPFL CC BY SA

Keywords

Biomolecules, Protein functions, Chemical mixtures, Materials

At the helm of this research is Professor David Drew from Stockholm University, whose team, in collaboration with researchers across Europe and Japan, has marveled at the intricate molecular choreography governing ATP translocation into the ER. By employing cutting-edge cryo-electron microscopy (cryo-EM), they elucidated high-resolution structures of SLC35B1, visualizing the transporter in multiple conformational states. These structural snapshots have unraveled the mechanistic underpinnings of how SLC35B1 effectively recognizes and facilitates the passage of ATP molecules from the cytosol into the ER interior, a compartment critical for cellular homeostasis.

The ER functions as a cellular nexus, orchestrating the synthesis, folding, and trafficking of proteins and lipids essential for cell survival. These energetically demanding processes rely heavily on ATP, whose precise delivery into the ER has remained an unresolved mystery due to the organelle’s isolation from direct ATP synthesis and cytosolic ATP pools. The confirmation of SLC35B1 as the ATP transporter fills this vital knowledge gap, fundamentally advancing our comprehension of intracellular energy logistics.

Intriguingly, the data show that SLC35B1 operates through a step-wise translocation mechanism, involving specific binding sites that selectively recognize ATP’s physiochemical properties. The cryo-EM structures detail key amino acid residues integral to ATP binding and conveyance, highlighting prospective molecular targets for drug design. By modulating these critical residues, future therapies could influence ATP transport efficiency, offering novel interventions for managing ER stress-related pathologies.

Diseases such as type 2 diabetes, various cancers, and neurodegenerative disorders like Alzheimer’s disease have all been linked to impaired ER function characterized by energy imbalance and protein misfolding. The ability to alter ATP supply within the ER through pharmacological agents targeting SLC35B1 is poised to revolutionize treatment paradigms. Enhanced ATP delivery could restore ER homeostasis in conditions marked by energy deficits, while downregulating transport might suppress aberrant activities in pathological states where ER stress fuels disease progression.

Particularly notable is the interdisciplinary approach behind this advance. Early attempts at identifying the ATP transporter candidate were confounded by conflicting reports and scant biochemical validation. To resolve this, the team leveraged a large-scale CRISPR/Cas9 knockout screening conducted collaboratively with the Giulio Superti-Furga Lab at Austria’s CeMM. This functional genomics approach ranked SLC35B1 among the top five crucial transporters for cellular viability, consolidating its role in ATP transport.

Further experimental validation came from the generation of a highly specific antibody against human SLC35B1 by Norimichi Nomura’s group at Kyoto Medical School. This antibody proved indispensable for stabilizing the transporter protein, effectively increasing its molecular size to a threshold amenable for cryo-EM imaging. Without this step, capturing detailed structural information of such a relatively small membrane protein would have remained elusive, demonstrating the ingenuity behind the methodological advancements.

Professor Drew emphasizes that the uncovered molecular blueprint extends beyond fundamental biology into translational medicine. By revealing SLC35B1’s conformational dynamics and ATP-binding motifs, the study provides a scaffold for the rational design of small molecules capable of fine-tuning transporter activity. Therapeutic modulation could either safeguard ER function by enhancing ATP import in disease states or inhibit it where pathological ER hyperactivity contributes to disease.

Currently, the research consortium is actively screening compound libraries for small molecules that can specifically interact with SLC35B1. These efforts aim to identify candidate molecules capable of modulating ATP transport, thereby paving the way for targeted therapies that rectify ER-related metabolic imbalances. Such drug candidates could usher in a new class of treatments addressing the root causes of ER-associated disorders.

The ramifications of this discovery also resonate with broader cellular physiology, as it sheds light on energy distribution mechanisms within organelles. Understanding how ATP is selectively delivered and consumed within intracellular compartments is a fundamental biological problem with implications across metabolism, signaling, and cell survival pathways. This study places SLC35B1 at the center of this intricate web, providing a tangible target for further exploration.

From a technical standpoint, the study showcases how modern structural biology techniques such as cryo-EM have transformed our ability to visualize membrane proteins in action. By capturing SLC35B1 in multiple functional states, the researchers not only confirm its role but also reveal the dynamic conformational landscape that underpins transporter function. This insight is essential for any future endeavors seeking to manipulate transporter behavior pharmacologically.

Ultimately, this seminal research on SLC35B1 catalyzes a paradigm shift in how we perceive organellar bioenergetics and its linkage to disease. As we deepen our grasp on molecular transport mechanisms, we open avenues to innovative therapeutic strategies that target intracellular energy pathways. The promise of controlling ATP flow within the ER is poised to impact a wide spectrum of diseases where cellular energy dysregulation is pathogenic.

In summary, the identification and detailed characterization of SLC35B1 as the human ER ATP transporter resolves a pivotal question in cell biology and medicine. This work exemplifies the power of multidisciplinary collaboration combining structural biology, biochemistry, genetics, and chemical biology to untangle complex cellular phenomena. With ongoing drug discovery efforts, the path from fundamental discovery to clinical application looks increasingly attainable, heralding a new frontier in combating ER-associated human diseases.

Subject of Research: Cells

Article Title: Step-wise ATP translocation into the ER by human SLC35B1

News Publication Date: 21-May-2025

Web References: https://www.nature.com/articles/s41586-025-09069-w

References: DOI: 10.1038/s41586-025-09069-w

Image Credits: Made by Surabhi Kokane using Biorender.com

Keywords: ATP transport, SLC35B1, endoplasmic reticulum, cryo-electron microscopy, membrane transporter, ER stress, protein folding, cellular bioenergetics, targeted therapy, molecular structure, CRISPR/Cas9 screening, drug discovery