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TitleMolecular mechanism of substrate recognition by folate transporter SLC19A1.
Journal, issue, pagesCell Discov, Vol. 8, Issue 1, Page 141, Year 2022
Publish dateDec 28, 2022
AuthorsYu Dang / Dong Zhou / Xiaojuan Du / Hongtu Zhao / Chia-Hsueh Lee / Jing Yang / Yijie Wang / Changdong Qin / Zhenxi Guo / Zhe Zhang /
PubMed AbstractFolate (vitamin B) is the coenzyme involved in one-carbon transfer biochemical reactions essential for cell survival and proliferation, with its inadequacy causing developmental defects or severe ...Folate (vitamin B) is the coenzyme involved in one-carbon transfer biochemical reactions essential for cell survival and proliferation, with its inadequacy causing developmental defects or severe diseases. Notably, mammalian cells lack the ability to de novo synthesize folate but instead rely on its intake from extracellular sources via specific transporters or receptors, among which SLC19A1 is the ubiquitously expressed one in tissues. However, the mechanism of substrate recognition by SLC19A1 remains unclear. Here we report the cryo-EM structures of human SLC19A1 and its complex with 5-methyltetrahydrofolate at 3.5-3.6 Å resolution and elucidate the critical residues for substrate recognition. In particular, we reveal that two variant residues among SLC19 subfamily members designate the specificity for folate. Moreover, we identify intracellular thiamine pyrophosphate as the favorite coupled substrate for folate transport by SLC19A1. Together, this work establishes the molecular basis of substrate recognition by this central folate transporter.
External linksCell Discov / PubMed:36575193 / PubMed Central
MethodsEM (single particle)
Resolution3.54 - 3.72 Å
Structure data

34817

8hii

EMDB-34817, PDB-8hii:
The BRIL-SLC19A1/Fab/Nb ternary complex
Method: EM (single particle) / Resolution: 3.57 Å

34818

8hij

EMDB-34818, PDB-8hij:
The 5-MTHF-bound BRIL-SLC19A1/Fab/Nb ternary complex
Method: EM (single particle) / Resolution: 3.54 Å

34819

8hik

EMDB-34819, PDB-8hik:
The TPP-bound BRIL-SLC19A1/Fab/Nb ternary complex
Method: EM (single particle) / Resolution: 3.72 Å

Chemicals

ChemComp-THH:
N-[4-({[(6S)-2-AMINO-4-HYDROXY-5-METHYL-5,6,7,8-TETRAHYDROPTERIDIN-6-YL]METHYL}AMINO)BENZOYL]-L-GLUTAMIC ACID

ChemComp-TPP:
THIAMINE DIPHOSPHATE

Source
  • homo sapiens (human)
  • lama glama (llama)
  • escherichia coli (E. coli)
KeywordsTRANSPORT PROTEIN / SLC19A1 / RFC / transporter / folates / BRIL / 5-MTHF / TPP

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