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| Title | Molecular Structure of the Na,K-ATPase α4β1 Isoform in Its Ouabain-Bound Conformation. |
|---|---|
| Journal, issue, pages | Int J Mol Sci, Vol. 25, Issue 22, Year 2024 |
| Publish date | Nov 19, 2024 |
 Authors | Kazuhiro Abe / Jeff McDermott / Hridya Valia Madapally / Parthiban Marimuthu / Chai C Gopalasingam / Christoph Gerle / Hideki Shigematsu / Himanshu Khandelia / Gustavo Blanco /      |
| PubMed Abstract | Na,K-ATPase is the active ion transport system that maintains the electrochemical gradients for Na and K across the plasma membrane of most animal cells. Na,K-ATPase is constituted by the association ...Na,K-ATPase is the active ion transport system that maintains the electrochemical gradients for Na and K across the plasma membrane of most animal cells. Na,K-ATPase is constituted by the association of two major subunits, a catalytic α and a glycosylated β subunit, both of which exist as different isoforms (in mammals known as α1, α2, α3, α4, β1, β2 and β3). Na,K-ATPase α and β isoforms assemble in different combinations to produce various isozymes with tissue specific expression and distinct biochemical properties. Na,K-ATPase α4β1 is only found in male germ cells of the testis and is mainly expressed in the sperm flagellum, where it plays a critical role in sperm motility and male fertility. Here, we report the molecular structure of Na,K-ATPase α4β1 at 2.37 Å resolution in the ouabain-bound state and in the presence of beryllium fluoride. Overall, Na,K-ATPase α4 structure exhibits the basic major domains of a P-Type ATPase, resembling Na,K-ATPase α1, but has differences specific to its distinct sequence. Dissimilarities include the site where the inhibitor ouabain binds. Molecular simulations indicate that glycosphingolipids can bind to a putative glycosphingolipid binding site, which could potentially modulate Na,K-ATPase α4 activity. This is the first experimental evidence for the structure of Na,K-ATPase α4β1. These data provide a template that will aid in better understanding the function Na,K-ATPase α4β1 and will be important for the design and development of compounds that can modulate Na,K-ATPase α4 activity for the purpose of improving male fertility or to achieve male contraception. |
 External links | Int J Mol Sci / PubMed:39596464 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 2.37 Å |
| Structure data | EMDB-60570, PDB-8zyj: |
| Chemicals |  ChemComp-MG:  ChemComp-NA:  ChemComp-CLR:  ChemComp-OBN:  ChemComp-Q7G:  ChemComp-PCW:  ChemComp-NAG:  ChemComp-HOH: |
| Source |
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 Keywords | TRANSPORT PROTEIN / P-type ATPase / sodium pump / Na+ / K+-ATPase / testis / human |
homo sapiens (human)