Voltage Sensitive Phosphatase
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Voltage sensitive phosphatases or voltage sensor-containing phosphatases, commonly abbreviated VSPs, are a
protein family A protein family is a group of evolutionarily related proteins. In many cases, a protein family has a corresponding gene family, in which each gene encodes a corresponding protein with a 1:1 relationship. The term "protein family" should not be ...
found in many species, including humans, mice, zebrafish, frogs, and sea squirt.


Discovery

The first voltage sensitive phosphatase was discovered as a result of a genome-wide search in the
sea squirt Ascidiacea, commonly known as the ascidians or sea squirts, is a paraphyletic class in the subphylum Tunicata of sac-like marine invertebrate filter feeders. Ascidians are characterized by a tough outer test or "tunic" made of the polysaccharid ...
''
Ciona intestinalis ''Ciona intestinalis'' (sometimes known by the common name of vase tunicate) is an ascidian (sea squirt), a tunicate with very soft tunic. Its Latin name literally means "pillar of intestines", referring to the fact that its body is a soft, tran ...
''. The search was designed to identify proteins which contained a sequence of
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
s called a
voltage sensor A sensor is often defined as a device that receives and responds to a signal or stimulus. The stimulus is the quantity, property, or condition that is sensed and converted into electrical signal. In the broadest definition, a sensor is a devi ...
, because this sequence of amino acids confers voltage sensitivity to
voltage-gated ion channel Voltage-gated ion channels are a class of transmembrane proteins that form ion channels that are activated by changes in a Cell (biology), cell's electrical membrane potential near the channel. The membrane potential alters the conformation of t ...
s. Although the initial genomic analysis was primarily concerned with the evolution of voltage-gated ion channels, one of the results of the work was the discovery of the VSP protein in sea squirt, termed Ci-VSP. The homologues to Ci-VSP in mammals are called Transmembrane phosphatases with tensin homology, or
TPTE Putative tyrosine-protein phosphatase TPTE is an enzyme that in humans is encoded by the ''TPTE'' gene. Function TPTE is a member of a large class of membrane-associated phosphatases with substrate specificity for the 3-position phosphate of i ...
s. TPTE (now also called hVSP2) and the closely related TPIP (also called TPTE2 or hVSP1) were identified before the discovery of Ci-VSP, however no voltage-dependent activity was described in the initial reports of these proteins. Subsequently, computational methods were used to suggest that these proteins may be voltage sensitive, however Ci-VSP is still widely regarded as the first-identified VSP.


Species and tissue distribution

VSPs are found across animals and
choanoflagellate Choanoflagellates are a group of free-living unicellular and colonial flagellate eukaryotes considered to be the closest living relatives of animals. The name refers to the characteristic funnel-shaped "collar" of interconnected microvilli and ...
s, though lost from nematodes and insects. Humans contain two members,
TPTE Putative tyrosine-protein phosphatase TPTE is an enzyme that in humans is encoded by the ''TPTE'' gene. Function TPTE is a member of a large class of membrane-associated phosphatases with substrate specificity for the 3-position phosphate of i ...
and TPTE2, which result from a primate-specific duplicatio

Most reports indicate that VSPs are found primarily in reproductive tissue, especially the testis. Other VSPs discovered include: Dr-VSP (
zebrafish The zebrafish (''Danio rerio'') is a species of freshwater ray-finned fish belonging to the family Danionidae of the order Cypriniformes. Native to South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio (an ...
''Danio rerio'', 2008, 2022), Gg-VSP (
chicken The chicken (''Gallus gallus domesticus'') is a domesticated subspecies of the red junglefowl (''Gallus gallus''), originally native to Southeast Asia. It was first domesticated around 8,000 years ago and is now one of the most common and w ...
''Gallus gallus domesticus'', 2014), Xl-VSP1, Xl-VSP2, and Xt-VSP (frogs: ''
X. laevis The African clawed frog (''Xenopus laevis''), also known as simply xenopus, African clawed toad, African claw-toed frog or the ''platanna'') is a species of African aquatic frog of the family Pipidae. Its name is derived from the short black cla ...
'' and ''
X. tropicalis The western clawed frog (''Xenopus tropicalis'') is a species of frog in the family Pipidae, also known as tropical clawed frog. It is the only species in the genus ''Xenopus'' to have a diploid genome. Its genome has been sequenced, making it a ...
'', 2011), TPTE (mouse), etc. Following the discovery of Ci-VSP, the nomenclature used for naming these proteins consists of two letters corresponding to the initials of the species name, followed by the acronym VSP. For the human VSPs, it has been suggested the adoption of the names Hs-VSP1 and Hs-VSP2 when referring to TPIP and TPTE, respectively.


Structure and function

VSPs are made up of two
protein domain In molecular biology, a protein domain is a region of a protein's Peptide, polypeptide chain that is self-stabilizing and that Protein folding, folds independently from the rest. Each domain forms a compact folded Protein tertiary structure, thre ...
s: a voltage sensor domain, and a
phosphatase In biochemistry, a phosphatase is an enzyme that uses water to cleave a phosphoric acid Ester, monoester into a phosphate ion and an Alcohol (chemistry), alcohol. Because a phosphatase enzyme catalysis, catalyzes the hydrolysis of its Substrate ...
domain coupled to a lipid-binding C2 domain.


The voltage sensor

The voltage sensor domain contains four transmembrane helices, named S1 through S4. The S4 transmembrane helix contains a number of positively charged arginine and lysine amino acid residues. Voltage sensitivity in VSPs is generated primarily by these charges in the S4, in much the same way that voltage-gated ion channels are gated by voltage. When
positive charge Electric charge (symbol ''q'', sometimes ''Q'') is a physical property of matter that causes it to experience a force when placed in an electromagnetic field. Electric charge can be ''positive'' or ''negative''. Like charges repel each other and ...
builds up on one side of a membrane containing such voltage sensors, it generates an electric force pressing the S4 in the opposite direction. Changes in membrane potential therefore move the S4 back and forth through the membrane, allowing the voltage sensor to act like a switch. Activation of the voltage sensor occurs at depolarized potentials, i.e.: when the membrane collects more positive charge on the inner leaflet. Conversely, deactivation of the voltage sensor takes place at hyperpolarized potentials, when the membrane collects more negative charge on the inner leaflet. Activation of the voltage sensor increases the activity of the phosphatase domain, while deactivation of the voltage sensor decreases phosphatase activity.


The phosphatase

The phosphatase domain in VSPs is highly homologous to the
tumor suppressor A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell (biology), cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results ...
PTEN, and acts to remove phosphate groups from
phospholipids Phospholipids are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typi ...
in the membrane containing the VSP. Phospholipids such as inositol phosphates are signaling molecules which exert different effects depending on the pattern in which they are phosphorylated and dephosphorylated. Therefore, the action of VSPs is to indirectly regulate processes dependent on phospholipids. The main substrate that has been characterized so far for VSPs (including hVSP1 but not hVSP2/
TPTE Putative tyrosine-protein phosphatase TPTE is an enzyme that in humans is encoded by the ''TPTE'' gene. Function TPTE is a member of a large class of membrane-associated phosphatases with substrate specificity for the 3-position phosphate of i ...
, which shows no phosphatase activity) is
phosphatidylinositol (4,5)-bisphosphate Phosphatidylinositol 4,5-bisphosphate or PtdIns(4,5)''P''2, also known simply as PIP2 or PI(4,5)P2, is a minor phospholipid component of cell membranes. PtdIns(4,5)''P''2 is enriched at the plasma membrane where it is a substrate for a number of ...
, which VSPs dephosphorylate at the 5' position. However, VSP activity has been reported against other
phosphoinositides Phosphatidylinositol or inositol phospholipid is a biomolecule. It was initially called "inosite" when it was discovered by Léon Maquenne and Johann Joseph von Scherer in the late 19th century. It was discovered in bacteria but later also found ...
as well, including
phosphatidylinositol (3,4,5)-trisphosphate Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)''P''3), abbreviated PIP3, is the product of the class I phosphoinositide 3-kinases' (PI 3-kinases) phosphorylation of phosphatidylinositol (4,5)-bisphosphate (PIP2). It is a phospholipid ...
, which is also dephosphorylated at the 5' position. Activity against the 3-phosphate of PI(3,4)P2 has also been demonstrated; this activity seems to become apparent at high membrane potentials, at lower potentials the 5'-phosphatase activity is predominant.


X-ray crystal structures

X-ray crystallography X-ray crystallography is the experimental science of determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to Diffraction, diffract in specific directions. By measuring th ...
has been used to generate high-resolution images of the two domains of Ci-VSP, separate from one another. By introducing small mutations in the protein, researchers have produced crystal structures of both the voltage sensing domain and the phosphatase domain from Ci-VSP in what are thought to be the "on" and "off" states. These structures have led to a model of VSP activation where movement of the voltage sensor affects a conformational change in a "gating loop," moving a glutamate residue in the gating loop away from the catalytic pocket of the phosphatase domain to increase phosphatase activity.


Uses in research and in biology

VSPs have been used as a tool to manipulate phospholipids in experimental settings. Because membrane potential can be controlled using
patch clamp The patch clamp technique is a laboratory technique in electrophysiology used to study ionic currents in individual Cell isolation, isolated living cells, tissue sections, or patches of cell membrane. The technique is especially useful in the st ...
techniques, placing VSPs in a membrane allows for experimenters to rapidly dephosphorylate substrates of VSPs. VSPs' voltage sensors have also been used to engineer various types of
genetically encoded voltage indicator Genetically encoded voltage indicator (or GEVI) is a protein that can sense membrane potential in a cell and relate the change in voltage to a form of output, often Fluorescence, fluorescent level. It is a promising Optogenetics, optogenetic record ...
(GEVI). These probes allow experimenters to visualize voltage in membranes using fluorescence. However, the normal role which VSPs play in the body is still not well understood.


See also

*
Gating (electrophysiology) In electrophysiology, the term gating refers to the opening (activation) or closing (by deactivation or inactivation) of ion channels. This change in conformation is a response to changes in transmembrane voltage. When ion channels are in a 'close ...
*
Genetically encoded voltage indicator Genetically encoded voltage indicator (or GEVI) is a protein that can sense membrane potential in a cell and relate the change in voltage to a form of output, often Fluorescence, fluorescent level. It is a promising Optogenetics, optogenetic record ...
*
Ion channel Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by Gating (electrophysiol ...
*
Phosphatase In biochemistry, a phosphatase is an enzyme that uses water to cleave a phosphoric acid Ester, monoester into a phosphate ion and an Alcohol (chemistry), alcohol. Because a phosphatase enzyme catalysis, catalyzes the hydrolysis of its Substrate ...


References

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