VAC14
Protein VAC14 homolog, also known as ArPIKfyve (Associated Regulator of PIKfyve), is a protein that in humans is encoded by the VAC14 gene.[5][6][7]
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. VAC14 functions as an activator of PIKFYVE.[5][8] 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.
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.[9] 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.[10] Human Vac14/ArPIKfyve also interacts with the PDZ (post-synaptic density) domain of neuronal nitric oxide synthase [11] but the functional significance of this interaction is still unclear. ArPIKfyve facilitates insulin-regulated GLUT4 translocation to the cell surface.[12]
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.[13] 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.[14]
VAC14 and human disease
The VAC14 gene is yet to be linked convincingly to human disease.[15]
References
- 1 2 3 GRCh38: Ensembl release 89: ENSG00000103043 - Ensembl, May 2017
- 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000010936 - Ensembl, May 2017
- ↑ "Human PubMed Reference:".
- ↑ "Mouse PubMed Reference:".
- 1 2 "Entrez Gene: Vac14 homolog (S. cerevisiae)".
- ↑ Davy BE, Robinson ML (May 2003). "Congenital hydrocephalus in hy3 mice is caused by a frameshift mutation in Hydin, a large novel gene". Hum. Mol. Genet. 12 (10): 1163–70. PMID 12719380. doi:10.1093/hmg/ddg122.
- ↑ Sbrissa D, Ikonomov OC, Strakova J, Dondapati R, Mlak K, Deeb R, Silver R, Shisheva A (December 2004). "A mammalian ortholog of Saccharomyces cerevisiae Vac14 that associates with and up-regulates PIKfyve phosphoinositide 5-kinase activity". Mol. Cell. Biol. 24 (23): 10437–47. PMC 529046
. PMID 15542851. doi:10.1128/MCB.24.23.10437-10447.2004. - ↑ Sbrissa D, Ikonomov OC, Fu Z, Ijuin T, Gruenberg J, Takenawa T, Shisheva A (August 2007). "Core protein machinery for mammalian phosphatidylinositol 3,5-bisphosphate synthesis and turnover that regulates the progression of endosomal transport. Novel Sac phosphatase joins the ArPIKfyve-PIKfyve complex". J. Biol. Chem. 282 (33): 23878–91. PMID 17556371. doi:10.1074/jbc.M611678200.
- ↑ Ikonomov OC, Sbrissa D, Fligger J, Delvecchio K, Shisheva A (August 2010). "ArPIKfyve regulates Sac3 protein abundance and turnover: disruption of the mechanism by Sac3I41T mutation causing Charcot-Marie-Tooth 4J disorder". J. Biol. Chem. 285 (35): 26760–4. PMC 2930674 . PMID 20630877. doi:10.1074/jbc.C110.154658.
- ↑ Sbrissa D, Ikonomov OC, Fenner H, Shisheva A (December 2008). "ArPIKfyve homomeric and heteromeric interactions scaffold PIKfyve and Sac3 in a complex to promote PIKfyve activity and functionality". J. Mol. Biol. 384 (4): 766–79. PMC 2756758 . PMID 18950639. doi:10.1016/j.jmb.2008.10.009.
- ↑ Lemaire JF, McPherson PS (December 2006). "Binding of Vac14 to neuronal nitric oxide synthase: Characterisation of a new internal PDZ-recognition motif". FEBS Lett. 580 (30): 6948–54. PMID 17161399. doi:10.1016/j.febslet.2006.11.061.
- ↑ Ikonomov OC, Sbrissa D, Dondapati R, Shisheva A (July 2007). "ArPIKfyve-PIKfyve interaction and role in insulin-regulated GLUT4 translocation and glucose transport in 3T3-L1 adipocytes". Exp. Cell Res. 313 (11): 2404–16. PMC 2475679 . PMID 17475247. doi:10.1016/j.yexcr.2007.03.024.
- ↑ Zhang Y, Zolov SN, Chow CY, Slutsky SG, Richardson SC, Piper RC, Yang B, Nau JJ, Westrick RJ, Morrison SJ, Meisler MH, Weisman LS (October 2007). "Loss of Vac14, a regulator of the signaling lipid phosphatidylinositol 3,5-bisphosphate, results in neurodegeneration in mice". Proc. Natl. Acad. Sci. U.S.A. 104 (44): 17518–23. PMC 2077288 . PMID 17956977. doi:10.1073/pnas.0702275104.
- ↑ Jin N, Chow CY, Liu L, Zolov SN, Bronson R, Davisson M, Petersen JL, Zhang Y, Park S, Duex JE, Goldowitz D, Meisler MH, Weisman LS (December 2008). "VAC14 nucleates a protein complex essential for the acute interconversion of PI3P and PI(3,5)P(2) in yeast and mouse". EMBO J. 27 (24): 3221–34. PMC 2600653 . PMID 19037259. doi:10.1038/emboj.2008.248.
- ↑ "VAC14 - Vac14 homolog (S. cerevisiae)". WikiGenes. Retrieved 2011-07-16.
Further reading
- Mireskandari A, Reid RL, Kashanchi F, et al. (1996). "Isolation of a cDNA clone, TRX encoding a human T-cell lymphotrophic virus type-I Tax1 binding protein.". Biochim. Biophys. Acta. 1306 (1): 9–13. PMID 8611628. doi:10.1016/0167-4781(96)00012-7.