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Phosphoinositide-3-kinase, class 3

PDB Code 3IHY Target Class Non-protein Kinase Target PIK3C3 Alias MGC61518, PIK3C3, Vps34 Disease Area/Function cancer, signalling Date Deposited Jul 31 2009 Authors SIPONEN, M.I., TRESAUGUES, L., ARROWSMITH, C.H., BERGLUND, H., BOUNTRA, C., COLLINS, R., EDWARDS, A.M., FLODIN, S., FLORES, A., GRASLUND, S., HAMMARSTROM, M., JOHANSSON, A., JOHANSSON, I., KARLBERG, T., KOTENYOVA, T., KOTZSCH, A., KRAGH NIELSEN, T., MARKOVA, N., MOCHE, M., NYMAN, T., PERSSON, C., ROOS, A., SAGEMARK, J., SCHUTZ P., SCHUELER, H., THORSELL, A.G., VAN DEN BERG, S., WAHLBERG, E., WEIGELT, J., WELIN, M., WISNIEWSKA, M., NORDLUND, P. Related Structure 3LS8

About this structure

Phosphatidylinositol (PtdIns) 3-kinases (PI3K) are enzymes that catalyse phosphorylation of the 3′ hydroxyl position of myo-inositol lipids. The enzymes can be divided into three major classes depending on their substrate specificity and subunit organisation [1]. PIK3C3 also named Vps34 (vacuolar protein sorting 34) is the sole member of the class III PI3K and consists of an N-terminal C2 domain, an accessory helical domain and a catalytic domain in the C-terminus. The substrate specificity of PIK3C3 is restricted to phosphatidylinositol and is thus distinguished from the other family members which also use phosphorylated derivatives of this phospholipid as substrate [2]. PIK3C3 is involved in regulation of vesicular trafficking in the endosomal system where the phosphatidylinositol triphosphate (PtdIns3P) produced acts to recruiting proteins that contains PtdIns3P binding domain [3]. PIK3C3 also regulates autophagy [4] and is implicated in neurodegenerative disease and in tumor suppression by having a role in the clearance of pathological protein aggregations. Furthermore PIK3C3 is implicated to have a role in regulating cellular response to nutrient deprivation [5].

Although only weak homology exists and the substrate binding region is unique for PIK3C3, the overall structure bears striking similarities to other PI3 kinases. The accessory domain folds as an α-helical structure. The catalytic domain consists of an N-terminal lobe and a C-terminal lobe separated by a cleft that forms the catalytic site of the enzyme, representing the typical architecture of protein and lipid kinases.

References

  1. Zhong Y, Wang QJ, Li X, Yan Y, Backer JM, Chait BT, Heintz N, Yue Z. (2009). Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex. Nat Cell Biol. 4:468-76.
  2. Byfield MP, Murray JT, Backer JM, (2005). hVps34 is a nutrient-regulated lipid kinase required for activation of p70 S6 kinase. J Biol Chem 38:33076-82.
  3. Backer JM (2008). The regulation and function of Class III PI3Ks: novel roles for Vps34. Biochem J. 1:1-17.
  4. Volinia S, Dhand R, Vanhaesebroeck B, MacDougall LK, Stein R, Zvelebil MJ, Domin J, Panaretou C, Waterfield MD. (1995). A human phosphatidylinositol 3-kinase complex related to the yeast Vps34p-Vps15p protein sorting system. EMBO J 14:3339-48.
  5. Djordjevic S, Driscoll PC (2002). Structural insight into substrate specificity and regulatory mechanisms of phosphoinositide 3-kinases. Trends Biochem Sci. 8:426-32.