Alternative titles; symbols
HGNC Approved Gene Symbol: PIK3C3
Cytogenetic location: 18q12.3 Genomic coordinates (GRCh38): 18:41,955,234-42,087,830 (from NCBI)
Phosphoinositide (PI) 3-kinases are involved in both receptor-mediated signal transduction and intracellular trafficking. In yeast, the vps34 gene product is a PI 3-kinase that mediates the active diversion of proteins from the secretory pathway to vacuoles. Mammals appear to have a family of PI 3-kinases, which also includes PIK3CG (601232) and PIK3CA (171834) (summary by Volinia et al., 1995).
Volinia et al. (1995) cloned the human homolog of the yeast vps34 PI 3-kinase. The full-length PIK3C3 cDNA encodes an 887-amino acid polypeptide that is 37% identical to yeast vps34 over its entire length. Its predicted and observed molecular mass is approximately 100 kD. By Northern blot analysis, the PIK3C3 gene was expressed as a 3.7-kb transcript in all human tissues examined.
Volinia et al. (1995) showed that PIK3C3 has a substrate specificity and ion requirements that are distinct from the other known mammalian PI 3-kinases. The PIK3C3 gene does not associate with the p85 regulatory subunit (171833) but does form a complex with p150 (602610), a mammalian homolog of another protein in the yeast vps pathway.
Crystal Structure
Miller et al. (2010) solved the crystal structure of Vps34 at 2.9-angstrom resolution, which revealed a constricted adenine-binding pocket, suggesting the reason that specific inhibitors of this class of PI3K have proven elusive. Both the phosphoinositide-binding loop and the carboxyl-terminal helix of Vps34 mediate catalysis on membranes and suppress futile adenosine triphosphatase cycles. Vps34 appears to alternate between a closed cytosolic form and an open form on the membrane. Structures of Vps34 complexes with a series of inhibitors revealed the reason that an autophagy inhibitor preferentially inhibits Vps34 and underpinned the development of new potent and specific Vps34 inhibitors.
Miller, S., Tavshanjian, B., Oleksy, A., Perisic, O., Houseman, B. T., Shokat, K. M., Williams, R. L. Shaping development of autophagy inhibitors with the structure of the lipid kinase Vps34. Science 327: 1638-1642, 2010. [PubMed: 20339072] [Full Text: https://doi.org/10.1126/science.1184429]
Volinia, S., Dhand, R., Vanhaesebroeck, B., MacDougall, L. K., Stein, R., Zvelebil, M. J., Domin, J., Panaretou, C., Waterfield, M. D. A human phosphatidylinositol 3-kinase complex related to the yeast Vps34p-Vps15p protein sorting system. EMBO J. 14: 3339-3348, 1995. [PubMed: 7628435] [Full Text: https://doi.org/10.1002/j.1460-2075.1995.tb07340.x]