Recognition of cyclic dinucleotides and folates by human SLC19A1

Area of Science:

• Structural Biology
• Molecular Transport
• Biochemistry

Background:

• Cyclic dinucleotides (CDNs) are vital signaling molecules, with 2'3'-cGAMP produced in response to cytosolic DNA.
• The solute carrier SLC19A1 facilitates cellular uptake of CDNs and folate nutrients, impacting immune responses and drug efficacy.
• Understanding SLC19A1 transport mechanisms for CDNs and folates is crucial for physiological and pathological processes.

Purpose of the Study:

• To elucidate the structural basis of substrate recognition and transport by human SLC19A1 (hSLC19A1).
• To investigate how hSLC19A1 differentiates between cyclic dinucleotides and folate-type substrates.
• To provide mechanistic insights into hSLC19A1 function and disease-associated mutations.

Main Methods:

• Cryo-electron microscopy (cryo-EM) to determine structures of hSLC19A1.
• Structural analysis of hSLC19A1 in substrate-free state and complex with CDNs, folate, and antifolate.
• Mutagenesis studies to validate structural findings and functional mechanisms.

Main Results:

• hSLC19A1 employs distinct mechanisms for recognizing CDN and folate-type substrates.
• Two CDN molecules bind as a unit in the hSLC19A1 cavity, while folate and antifolate bind as monomers in a separate pocket.
• Structures provide insights into loss-of-activity and disease-related mutations in hSLC19A1.

Conclusions:

• The study reveals unique transport mechanisms for CDNs and folate-type substrates by hSLC19A1.
• These findings offer a framework for understanding SLC19-family transporters.
• The research lays the groundwork for developing novel therapeutics targeting SLC19A1.