A team of scientists has answered a long-standing question in cell biology, uncovering how the cell's main energy currency, ATP, is transported into the endoplasmic reticulum (ER). Disrupted energy transport could affect diseases such as type 2 diabetes, cancer, and neurodegenerative disorders. The study, published in Nature, confirms that the transporter protein SLC35B1 is the key gateway for ATP entry into the ER.
The research, led by David Drew, Professor of biochemistry at Stockholm University and located at SciLifeLab, reveals the first structural and mechanistic insight into how ATP enters the endoplasmic reticulum (ER) using the transporter protein SLC35B1. The ER is the cells main "shipping port" that packages proteins and lipids, checks their quality, and facilitates their transport within the cell. For these vital processes, energy in the form of ATP, is required.
"Despite decades of research into ER function, the question of how ATP reaches the inside of the ER has been unclear. By confirming SLC35B1 as the transporter and resolving its structure with cryo-electron microscopy, we've not only answered a fundamental biological question, but also opened up new opportunities for therapeutic intervention", says David Drew.
Future drug development
The findings have broad implications for human health. Disrupted ER activity is linked to diseases such as type 2 diabetes, cancer, and neurodegenerative disorders, where ER stress and protein misfolding play central roles. With a detailed molecular blueprint now available, SLC35B1 presents a promising target for future drug development.
"Understanding how energy is delivered into the ER gives us powerful new ways to tackle a range of diseases that stem from ER dysfunction. Modulating SLC35B1 activity could become a new strategy for restoring ER balance in disease states", says David Drew.
Large scale screen
SLC35B1 has previously been proposed as an ATP transporter for the ER (Nature Comms 9:3489), but biochemical and structural validation was lacking. There have also been other, conflicting reports about its function. Teaming up with Giulio Superti-Furga Lab (CeMM, Austria), a large-scale CRISPR/Cas9 knockout screen of all SLC transporters showed that SLC35B1 was one of the five most essential transporters for cell growth, consistent with its proposed function.
Increasing protein size
An antibody against human SLC35B1 was then generated by Norimichi Nomura's team (Kyoto Medical School, Japan), which was essential for increasing the size of the protein so it could be imaged by cryo-electron microscopy (cryo-EM). David Drew's team then used the cryo-EM platform at SciLifeLab to visualize SLC35B1 in multiple conformations, revealing how it recognizes and transports ATP into the endoplasmic reticulum lumen. The structural data also highlighted critical amino acid residues involved in ATP binding and transport, suggesting potential sites for therapeutic targeting.
Targeted therapies
The team is currently screening for small molecules that modulate SLC35B1 function, with the goal of developing targeted therapies to either enhance or inhibit ATP transport when needed.
Find the whole study in Nature: "Step-wise ATP translocation into the ER by human SLC35B1"
DOI: 10.1038/s41586-025-09069-w
