Protein VAC14 homolog, also known as ArPIKfyve (Associated Regulator of PIKfyve), is a protein

Protein

Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

 that in humans is encoded by the VAC14 gene

Gene

A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

.

Functions and interactions

The content of phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) in endosomal membranes changes dynamically with fission and fusion events that generate or absorb intracellular transport vesicles. The ArPIKfyve protein scaffolds a trimolecular complex to tightly regulate the level of PtdIns(3,5)P2. Other components of this complex are the PtdIns(3,5)P2-synthesizing enzyme PIKFYVE  and the Sac1-domain-containing PtdIns(3,5)P2 5-phosphatase Sac3, encoded by the human gene FIG4

Fig4

Polyphosphoinositide phosphatase also known as phosphatidylinositol 3,5-bisphosphate 5-phosphatase or SAC domain-containing protein 3 is an enzyme that in humans is encoded by the FIG4 gene.- Function :...

. VAC14 functions as an activator of PIKFYVE. Studies in VAC14 knockout mice indicate that, in addition to increasing the PtdIns(3,5)P2-producing activity of PIKfyve, VAC14 also controls the steady-state levels of another rare phosphoinositide linked to PIKfyve enzyme activity – phosphatidylinositol 5-phosphate

Phosphatidylinositol 5-phosphate

Phosphatidylinositol 5-phosphate is one of the seven phosphoinositides, and is the last to have been discovered to be naturally occurring....

.

In addition to the formation of the ternary complex with PIKfyve and Sac3, ArPIKfyve is engaged in a number of other interactions. ArPIKfyve forms a stable complex with the PtdIns(3,5)P2-specific phosphatase Sac3, thereby protecting Sac3 from rapid degradation in the proteasome. ArPIKfyve forms a homooligomer through its carboxyl terminus. However, the number of monomers in the ArPIKfyve homooligomer, ArPIKfyve-Sac3 heterodimer or PIKfyve-ArPIKfyve-Sac3 heterotrimer is unknown. Human Vac14/ArPIKfyve also interacts with the PDZ (post-synaptic density) domain of neuronal nitric oxide synthase but the functional significance of this interaction is still unclear. ArPIKfyve facilitates insulin-regulated GLUT4 translocation to the cell surface.

Lessons from VAC14 mouse models

VAC14 knock-out mice die at, or shortly after birth and exhibit massive neurodegeneration. Fibroblasts from these mice display ~50% lower levels of PtdIns(3,5)P2 and PtdIns(5)P. A spontaneous mouse VAC14-point mutation (with arginine substitution of leucine156) is associated with reduced life span (up to 3 weeks), body size, enlarged brain ventricles, 50% decrease in PtdIns(3,5)P2 levels, diluted pigmentation, tremor and impaired motor function.