Cellular Condensates Have Hidden Structure, Offering New Drug Targets

Cells, the fundamental units of life, are increasingly understood to organize their inner workings not through rigid structures, but through dynamic, droplet-like assemblies called biomolecular condensates. These condensates, unlike organelles bound by membranes, form through the interactions of proteins and nucleic acids, controlling vital processes from gene expression to waste removal. Recent research suggests these condensates aren’t simply amorphous blobs, but possess a hidden architecture that could unlock new therapeutic avenues for diseases like cancer and amyotrophic lateral sclerosis (ALS).

Unveiling Internal Frameworks

A study published in Nature Structural and Molecular Biology on February 2, 2026, challenges the long-held view of biomolecular condensates as unstructured droplets. Researchers at Scripps Research discovered that certain condensates are built from intricate networks of protein filaments – thin, thread-like structures that give the droplets a defined internal organization. This architecture isn’t merely a structural detail; it’s crucial for how these condensates function. The findings suggest a new approach to treating diseases where condensate disruption plays a key role.

“Ever since we realized that disruptions in condensate formation are at the heart of many diseases, it has been challenging to target them therapeutically because they appeared to lack structure — there were no specific features for a drug to latch onto,” explains Keren Lasker, associate professor at Scripps Research and senior author of the study. “This work changes that. You can now see that some condensates have an internal architecture, and that, importantly, this structure is required for function, opening the door to targeting these membrane-less assemblies much like we target individual proteins.”

The PopZ Protein: A Bacterial Model

To investigate how condensates function without membranes, Lasker’s team focused on a bacterial protein called PopZ. In rod-shaped bacteria, PopZ accumulates at the cell poles – the rounded ends – forming condensates that organize proteins essential for cell division. Using cryo-electron tomography (cryo-ET), a high-resolution imaging technique akin to a CT scan at the molecular level, the researchers visualized PopZ proteins assembling into filaments in a precise, step-by-step manner. These filaments then create a scaffold that dictates the condensate’s physical properties. Biomolecular condensates are increasingly recognized as key regulators of cellular processes.

Protein Shape-Shifting Within Condensates

The research went further, examining how individual PopZ molecules behave. Employing single-molecule Förster resonance energy transfer (FRET), a technique that detects minute distance changes within proteins by measuring energy transfer between fluorescent tags, the team found that PopZ changes shape depending on its location. The protein adopts one conformation outside a condensate and a different one inside.

“Realizing that protein conformation depends on location gives us multiple ways to engineer cellular function,” says Daniel Scholl, first author and former postdoctoral researcher in the Lasker and Deniz labs.

Filament Structure: Essential for Life

To determine if the filaments were merely structural components or functionally critical, the team engineered a mutant version of PopZ unable to form filaments. The resulting condensates became more fluid and exhibited lower surface tension. Introducing these changes into living bacteria halted growth and disrupted DNA separation, demonstrating that the condensate’s physical properties – not just its chemical composition – are vital for normal cellular function.

Implications for Human Disease

While the experiments were conducted in bacteria, the findings have significant implications for human health. In human cells, filament-based condensates perform two crucial tasks: clearing damaged or toxic proteins and regulating cell growth. Breakdown of these cleanup condensates leads to the accumulation of harmful proteins, a hallmark of neurodegenerative diseases like ALS. Conversely, failure of growth-regulating condensates can compromise tumor-suppressing mechanisms, contributing to cancers such as prostate, breast, and endometrial cancers. Co-condensation of proteins with DNA is a key aspect of condensate formation.

“By demonstrating that condensate architecture is both definable and functionally critical, the work raises the possibility of designing therapies that act directly on condensate structure and correct the underlying disorganization that allows disease to take hold,” Lasker states.

What Comes Next: Refining Therapeutic Targets

The Scripps Research team’s findings represent a significant step forward in understanding the complex organization of biomolecular condensates. Future research will focus on identifying the specific mechanisms that regulate filament formation and condensate architecture in human cells. This knowledge will be crucial for developing targeted therapies that can restore proper condensate function in disease states. Further investigation is needed to determine the prevalence of filament-based condensates across different cell types and disease contexts. Clinical trials evaluating the efficacy of condensate-targeting therapies are still several years away, but this research provides a promising foundation for future drug development efforts. The study authors also note the need for continued exploration of the interplay between protein conformation and condensate function, as this could reveal additional therapeutic targets.

In addition to Lasker, Scholl, Deniz, and Park, authors of the study, “The filamentous ultrastructure of the PopZ condensate is required for its cellular function,” include Tumara Boyd, Andrew P. Latham, Alexandra Salazar, Asma Khan, Steven Boeynaems, Alex S. Holehouse, Gabriel C. Lander and Andrej Sali.

The research was supported by the National Institutes of Health (NINDS DP2 NS142714, NIGMS F32 GM150243, NIGMS R01 GM083960, NINDS R01 NS095892, NIGMS RO1 GM14305, NIGMS R35 GM130375, and ORIPS10 OD032467), the National Science Foundation (2235200 and DBI 2213983), the Water and Life Interface Institute, the Gordon & Betty Moore Foundation (Moore Inventor Fellowship 579361), and the Cancer Prevention and Research Institute of Texas (RR220094).