Florman Lab Publications


Evolution of the Voltage Sensor Domain of the Voltage-Sensitive Phosphoinositide Phosphatase, VSP/TPTE, Suggests a Role as a Proton Channel in Eutherian Mammals

UMMS Affiliation

Department of Cell Biology

Publication Date


Document Type



Phosphoric Monoester Hydrolases; PTEN Phosphohydrolase; Membrane Proteins; Ion Channels


Cell Biology


The voltage-sensitive phosphoinositide phosphatases provide a mechanism to couple changes in the transmembrane electrical potential to intracellular signal transduction pathways. These proteins share a domain architecture that is conserved in deuterostomes. However, gene duplication events in primates, including humans, give rise to the paralogs TPTE and TPTE2 that retain protein domain organization but, in the case of TPTE, have lost catalytic activity. Here, we present evidence that these human proteins contain a functional voltage sensor, similar to that in nonmammalian orthologs. However, domains of these human proteins can also generate a noninactivating outward current that is not observed in zebra fish or tunicate orthologs. This outward current has the anticipated characteristics of a voltage-sensitive proton current and is due to the appearance of a single histidine residue in the S4 transmembrane segment of the voltage sensor. Histidine is observed at this position only during the eutherian radiation. Domains from both human paralogs generate proton currents. This apparent gain of proton channel function during the evolution of the TPTE protein family may account for the conservation of voltage sensor domains despite the loss of phosphatase activity in some human paralogs.

DOI of Published Version



Mol Biol Evol. 2012 Mar 28. Link to article on publisher's site

Journal/Book/Conference Title

Molecular biology and evolution

Related Resources

Link to Article in PubMed

PubMed ID