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TitleMechanistic studies of the human NIPA2 transporter.
Journal, issue, pagesNat Commun, Year 2026
Publish dateJul 21, 2026
AuthorsSebastian J Karuppan / Nikolas Connolly / Simran Shrestha / Matthew Medearis / Maryam Gholampour / Lejla Zubcevic /
PubMed AbstractThe Non-Imprinted in Prader-Willi/Angelman syndrome 2 (NIPA2) is a highly conserved member of the Drug/Metabolite Transporter (DMT) family, originally characterized as a Mg transporter. Dysfunction ...The Non-Imprinted in Prader-Willi/Angelman syndrome 2 (NIPA2) is a highly conserved member of the Drug/Metabolite Transporter (DMT) family, originally characterized as a Mg transporter. Dysfunction of NIPA2 has been linked to epilepsy and seizures but despite this the molecular mechanisms of transport and substrate recognition, as well as the functional and structural effects of patient mutations. To answer these questions and gain a fundamental understanding of NIPA2, we performed cryo-EM, and liposomal and cell-based assays. Here we show that NIPA2 passively transports both Mg and nucleotides, revealing a broader substrate profile than previously appreciated with potential physiological implications. Furthermore, we establish that NIPA2 utilizes an alternating-access mechanism that appears distinct from classical elevator and rocker switch models. Finally, we show that mutation A75T, linked to childhood absence epilepsy, results in loss of function. Our data provides a framework for understanding the physiological role of NIPA2 and related proteins.
External linksNat Commun / PubMed:42481511
MethodsEM (single particle)
Resolution3.5 - 3.9 Å
Structure data

73843

9z6n

EMDB-73843, PDB-9z6n:
Human NIPA2 transporter in the presence of EDTA
Method: EM (single particle) / Resolution: 3.7 Å

73878

9z7r

EMDB-73878, PDB-9z7r:
Human NIPA2 with magnesium
Method: EM (single particle) / Resolution: 3.5 Å

73879

9z7s

EMDB-73879, PDB-9z7s:
Human NIPA2 mutant A75T
Method: EM (single particle) / Resolution: 3.5 Å

73880

9z7t

EMDB-73880, PDB-9z7t:
Human NIPA2 with ATP
Method: EM (single particle) / Resolution: 3.9 Å

Chemicals

ChemComp-MG:
Unknown entry

ChemComp-HOH:
WATER

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

Source
  • homo sapiens (human)
KeywordsTRANSPORT PROTEIN / membrane protein / transporter

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