Phosphatase Subfamily VSP

Phosphatase Classification: Superfamily CC1: Family PTEN: Subfamily VSP

VSP is a transmembrane protein with a lipid phosphatase that is activated by a voltage sensor and controls activity of ion channels.

Evolution

VSPs are holozoan-specific and lost in insects and nematodes (but found in arachnids). There are two human genes, TPTE (PTEN2) and TPTE2 (TPIP). TPTE is a primate-specific duplicate of the TPTE2 locus (found in human and Gorilla, but not in chimp) There are 7 subfamily pseudogenes, some of which are expressed in testis, and at least one of which is conserved in orangutan.

Domain Structure

VSPs consist of an N-terminal voltage sensor with four transmembrane regions, followed by a phosphatase domain and a C2 domain. The C2 domain modulates VSP's function by interacting with the membrane [1].

Functions

Both human genes are testis specific (GTEx: TPTE, TPTE2), though some expression in brain and stomach has been reported. The single mouse gene is localized to the Golgi apparatus [2], while TPTE has been reported to be on the plasma membrane, while splice variants of TPTE2 are found in the ER or in the cytoplasm [3].

TPTE is predicted to be catalytically inactive, and TPTE2 has been shown to have phosphoinositide 3-phosphatase activity [3].

The Ciona homolog, Ci-VSP encodes a functional voltage-sensing domain expressed in sperm, and transduces membrane depolarization into alteration of phosphoinositide levels [4]. Ci-VSP has phosphatase activity against PI(3,4,5)P3 and PI(4,5)P2 [5]. The PI(4,5)P2 activity is not seen in PTEN, and change in levels of PI(4,5)P2 affects the activity of a family of potassium channels. CI-VSP has also been seen expressed in stomach and blood cells [6].

References

1. Castle PM, Zolman KD, and Kohout SC. Voltage-sensing phosphatase modulation by a C2 domain. Front Pharmacol. 2015;6:63. DOI:10.3389/fphar.2015.00063 |
2. Guipponi M, Tapparel C, Jousson O, Scamuffa N, Mas C, Rossier C, Hutter P, Meda P, Lyle R, Reymond A, and Antonarakis SE. The murine orthologue of the Golgi-localized TPTE protein provides clues to the evolutionary history of the human TPTE gene family. Hum Genet. 2001 Dec;109(6):569-75. DOI:10.1007/s004390100607 |
3. Walker SM, Downes CP, and Leslie NR. TPIP: a novel phosphoinositide 3-phosphatase. Biochem J. 2001 Dec 1;360(Pt 2):277-83. DOI:10.1042/0264-6021:3600277 |
4. Murata Y, Iwasaki H, Sasaki M, Inaba K, and Okamura Y. Phosphoinositide phosphatase activity coupled to an intrinsic voltage sensor. Nature. 2005 Jun 30;435(7046):1239-43. DOI:10.1038/nature03650 |
5. Iwasaki H, Murata Y, Kim Y, Hossain MI, Worby CA, Dixon JE, McCormack T, Sasaki T, and Okamura Y. A voltage-sensing phosphatase, Ci-VSP, which shares sequence identity with PTEN, dephosphorylates phosphatidylinositol 4,5-bisphosphate. Proc Natl Acad Sci U S A. 2008 Jun 10;105(23):7970-5. DOI:10.1073/pnas.0803936105 |
6. Ogasawara M, Sasaki M, Nakazawa N, Nishino A, and Okamura Y. Gene expression profile of Ci-VSP in juveniles and adult blood cells of ascidian. Gene Expr Patterns. 2011 Mar-Apr;11(3-4):233-8. DOI:10.1016/j.gep.2010.12.004 |