Recognition of cyclic dinucleotides and folates by human SLC19A1

Zhang, Qixiang; Zhang, Xuyuan; Zhu, Yalan; Sun, Panpan; Zhang, Liwei; Ma, Junxiao; Zhang, Yong; Zeng, Lingan; Nie, Xiaohua; Gao, Yina; Li, Zhaolong; Liu, Songqin; Lou, Jizhong; Gao, Ang; Zhang, Liguo; Gao, Pu

doi:10.1038/s41586-022-05452-z

Cited by 30 publications

(34 citation statements)

References 59 publications

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“…S7b ). Moreover, the interaction mode between SLC19A1 and 5-MTHF was very similar in our and Zhang et al’s studies, even though the conformations of the pterin ring and glutamate moieties of 5-MTHF showed some differences 51 , indicating these regions might possess some degree of flexibility upon binding to SLC19A1 (Supplementary Fig. S7b, c ).…”

Section: Discussionsupporting

confidence: 83%

“…It is also known that additional organicphosphate anionic molecules like ZMP (or AICAR, 5-aminoimidazole 4-carboxamide ribonucleoside) and cGAMP (2'3'-cyclic-GMP-AMP) were potential substrates of SLC19A1 [46][47][48][49] . After submission of our manuscript, two separate studies reported the structures of SLC19A1 in complexes with some other substrates, including Nhydroxysuccinimide-conjugated MTX (NHS-MTX), pemetrexed (PMX), and different cyclic dinucleotides (CDNs) 50,51 . SLC19A1 exhibited the same inward-facing conformation in all of these structures (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

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Molecular mechanism of substrate recognition by folate transporter SLC19A1

Dang

Zhou

et al. 2022

Cell Discov

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Folate (vitamin B9) 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.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Molecular mechanism of substrate recognition by folate transporter SLC19A1

Dang

Zhou

et al. 2022

Cell Discov

View full text Add to dashboard Cite

show abstract

“…It is also known that additional organic-phosphate anionic molecules like ZMP (or AICAR, 5aminoimidazole 4-carboxamide ribonucleoside) and cGAMP (2'3'-cyclic-GMP-AMP) were potential substrates of SLC19A1 [46][47][48][49] . After the submission of our manuscript, two separate studies reported the structures of SLC19A1 in complexes with some other substrates, including Nhydroxysuccinimide-conjugated MTX (NHS-MTX), pemetrexed (PMX), and different cyclic dinucleotides (CDNs) 50,51 . SLC19A1 exhibited the same inward-facing conformation in all of these structures (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanism of substrate recognition by folate transporter SLC19A1

Dang

Zhou

et al. 2022

Preprint

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Folate (vitamin B9) 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 has been unclear. Here we report the cryo-EM structures of human SLC19A1 and its complex with 5-methyltetrahydrofolate at 3.5-3.6 angstrom resolution and elucidate the critical residues for substrate recognition. In particular, we reveal that two variant residues among SLC19 subfamily members would designate the specificity for folate. Moreover, we identify intracellular thiamine pyrophosphate as the favorite coupled substrate for folate transport by SLC19A1. Together, this work has established the molecular basis of substrate recognition by this central folate transporter.

show abstract

“…5a). Cryo-EM-derived structures of SLC19A1 in the apo state and bound to 2′3′-cGAMP, the thiophosphate analog of 2′3′-cGAMP (2′3′-cGAMP S ) and 3′3′-cAA have been solved 92 . The 12 TMs of hSLC19A1 adopt a canonical major facilitator superfamily fold composed of TM1-TM6 and TM7-TM12 segments that together adopt an inward-open conformation, whose cryo-EM structure was solved in the apo state through utilization of a nanodisc-reconstituted hSLC19A1-antigen-binding fragment (hSLC19A1-Fab) system (Fig.…”

Section: Review Articlementioning

confidence: 99%

“…SLC19A1 (refs. 92,93 ) and the related SLC46A1 (ref. 94 ) are major transporters for folate cofactors and antifolate therapeutics, with insights into ligand capture having emerged from cryo-EM studies of their complexes.…”

Section: Review Articlementioning

confidence: 99%