In a breakthrough study, researchers have decoded how ATP—the cell’s main energy currency—enters the endoplasmic reticulum, solving a biological mystery and paving the way for therapies against diabetes, cancer, and neurodegenerative diseases.
Key Points at a Glance
- SLC35B1 identified as the transporter of ATP into the endoplasmic reticulum (ER)
- Structural insights obtained using cryo-electron microscopy
- ATP fuels protein folding and trafficking within the ER
- Disrupted ER energy balance linked to diabetes, cancer, and brain diseases
- Findings open new avenues for targeted therapies
Cells are bustling factories—and one of their busiest departments is the endoplasmic reticulum (ER), the organelle responsible for packaging, folding, and dispatching proteins and lipids. To do this critical job, the ER needs energy. But how does ATP, the molecular unit of currency for energy in cells, get inside the ER?
This long-standing puzzle in cell biology has finally been solved. In a study published in Nature, researchers led by Professor David Drew at Stockholm University have uncovered how ATP is transported into the ER: via a specific protein transporter named SLC35B1.
“Despite decades of research into ER function, this was a missing link,” says Drew. “By visualizing SLC35B1 and confirming its function, we now understand how this vital energy transaction takes place inside our cells.”
The team used cryo-electron microscopy (cryo-EM) to capture high-resolution images of SLC35B1 in action. Located in the ER membrane, this transporter acts as a molecular gateway, shuttling ATP from the cytosol into the ER lumen—an interior compartment where protein folding and quality control occur.
The study revealed the structure of SLC35B1 in multiple conformations, shedding light on how it binds ATP and guides it across the membrane. Critical amino acids involved in this process were identified, offering potential targets for therapeutic intervention.
The implications are profound. Energy delivery into the ER is essential for cellular homeostasis. Disruptions in this process can lead to ER stress, which is associated with diseases ranging from type 2 diabetes to Alzheimer’s and certain forms of cancer. With a detailed blueprint now available, scientists can explore how to modulate this pathway in disease settings.
To validate SLC35B1’s essential role, the research team collaborated with the Giulio Superti-Furga Lab at CeMM in Austria. They conducted a comprehensive CRISPR/Cas9 knockout screen, targeting all solute carrier (SLC) transporters. SLC35B1 emerged as one of the five most essential for cell growth—supporting its fundamental role in ATP delivery.
Generating structural data wasn’t easy. SLC35B1 is a small protein, making it difficult to visualize with cryo-EM. To solve this, the team partnered with Norimichi Nomura’s group at Kyoto Medical School, who developed a specific antibody to increase the protein’s effective size—making it visible under the microscope.
With SLC35B1’s structure in hand, the team is now working on screening small molecules that can enhance or inhibit its function. The hope is to develop drugs that restore balance in the ER for patients suffering from diseases where protein folding and energy management go awry.
“This discovery gives us a new therapeutic target at the cellular power distribution level,” says Drew. “We’re not just managing symptoms—we’re now aiming at the heart of cellular energy logistics.”
By illuminating how cells energize their protein-handling infrastructure, the study sets the stage for a new class of treatments—rooted in the most fundamental biology of life itself.
Source: Stockholm University
