Tuesday, 15 November 2011

Evolution of NaK-ATPase and ENaC: Part I: Na,K ATPase evolution in three steps

The Na,K-ATPase is a pump that transports actively the potassium and the sodium. Based in the basolateral side of the renal cell, it pumps out the sodium (3 Na+) and pump in the potassium (2 K+).

Author: LadyofHats Mariana Ruiz Villarreal
The Na,K-ATPase is a membrane protein and is composed by three subunits: the α-subunit (grey), the β-subunit (blue) and the γ-subunits (yellow).

Author: me, with PyMol and PDB:2QTS

The α-subunit is the functional unit of the pump. The β-subunit is important to help the pump to be fully functional (as a role of chaperone and membrane targeting), to operate in a bidirectional manner. Without the β-subunit, the pump is only unidirectional. The γ-subunit has only a small role, as a potassium modulator.

To analyse the evolutionary history of the NaK-ATPase, I performed phylogenetic analyses. Briefly, I applied psi-blast searches against the ncbi (nr dataset), swissprot and various eukaryotic genomes. Then I align the homologous sequences and I build the trees under maximum likehood (ML) and minimum evolution (ME) framework.

Step 1: α-subunit
As expected and already published (Saez et al. 2009), I found the α-subunit in the three kingdoms of life, suggesting that the α-subunit was already present in the Last Universal Common Ancestor (LUCA). Remember that at this stage, the NaK-ATPase is partially functional.

Step 2: β-subunit
The β-subunit appeared later, in the Holozoan ancestor. The Holozoan is a clade that encompass Metazoan (Animals) and Choanoflagellates (ie Monosiga). This finding is important, as the β-subunit helps the Na,K-ATPase to be fully functional. This means that the cell can now have the ability to create and control an internal milieu. This is true for Metazoan. But also for Choanoflagellates which, while being single-cell organisms, can form colonies (see picture below). The ancestor of Metazoan, the Urmetazoan, could have greatly benefited from this function to established its first internal milieu.
Sphaeroeca, a colony of choanoflagellates (aprox. 230 individuals)
Author: Dhzanette

Step 3: γ-subunit
As the γ-subunit possesses the short motif FYYD, it belongs to the FXYD protein family, which appeared later in the Vertebrates evolution (an exemplar of FXYD protein has been found in Sharks). This family has been diversified by the double round of genome duplication (2R WGD). The γ-subunit (also called FXYD2) appeared later in Tetrapodes, interestingly at the same time than the aldosterone hormone, which controls the Na,K-ATPase in kidney.
Another discovery from this study was the genes FXYD6 and FXYD8, which arose from a gene duplication at the origin in primates. The FXYD6 is implied in schizophrenic disease in human. Does the FXYD8 has an important role in brain too? However, lot of indices conclude that the FXYD8 is only a pseudogene. But due to its high level of identity between primates, I would not be surprised if a study will find something interesting on it.

In conclusion, the Na,K-ATPase is likely to be a key component of the multicellularity in Metazoans and was formed in three evolutionary steps:

Tomorrow, I will speak about its best friend, the ENaC/Degenerin channel.


Studer, R.A., Person, E., Robinson-Rechavi, M., & Rossier, B.C. (2011). Evolution of the epithelial sodium channel and the sodium pump as limiting factors of aldosterone action on sodium transport Physiological Genomics, 43 (13), 844-854 DOI: 10.1152/physiolgenomics.00002.2011

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