An intramolecular interaction within the lipid kinase Fab1 regulates cellular phosphatidylinositol 3,5-bisphosphate lipid levels.
Phosphorylated phosphoinositide lipids (PPIs) are low-abundance signaling molecules that control signal transduction pathways and are necessary for cellular homeostasis. The PPI phosphatidylinositol (3,5)-bisphosphate (PI(3,5)P2) is essential in multiple organ systems. PI(3,5)P2is generated from PI3P by the conserved lipid kinase Fab1/PIKfyve. Defects in the dynamic regulation of PI(3,5)P2are linked to human diseases. However, few mechanisms that regulate PI(3,5)P2have been identified. Here we report an intramolecular interaction between the yeast Fab1 kinase region and an upstream conserved cysteine-rich (CCR) domain. We identify mutations in the kinase domain that lead to elevated levels of PI(3,5)P2and impair the interaction between the kinase and CCR domain. We also identify mutations in the CCR domain that lead to elevated levels of PI(3,5)P2Together these findings reveal a regulatory mechanism that involves the CCR domain of Fab1 and contributes to dynamic control of cellular PI(3,5)P2synthesis.
Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109.|Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109.
Michael J
MJ
Lang
Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109.
Bethany S
BS
Strunk
Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109.
Nadia
N
Azad
Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109.
Jason L
JL
Petersen
Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109 lweisman@umich.edu.|Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109.
Lois S
LS
Weisman
D003553:Cystine; D006706:Homeostasis; D008055:Lipids / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism* / Q000502:physiology; D010716:Phosphatidylinositols; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism* / Q000502:physiology; D000072417:Protein Domains; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction
D003553:Cystine; D008055:Lipids; D019869:Phosphatidylinositol 3-Kinases; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; D010716:Phosphatidylinositols; D017853:Phosphotransferases (Alcohol Group Acceptor); D029701:Saccharomyces cerevisiae Proteins; C106336:phosphatidylinositol 3,5-diphosphate; C095504:FAB1 protein, S cerevisiae