7K1W

PIKfyve/Fig4/Vac14 complex centered on Fig4 - map3

Summary for 7K1W

• Entry DOI: 10.2210/pdb7k1w/pdb
• EMDB information: 22631 22634 22647
• Descriptor: Fig4 Sac homology model (1 entity in total)
• Functional Keywords: lipid kinase, lipid phosphatase, protein complex, lipid binding protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 105144.29

Authors

Lees, J.A.,Reinisch, K.M.,Li, P. (deposition date: 2020-09-08, release date: 2020-10-21, Last modification date: 2025-06-04)

Primary citation

Lees, J.A.,Li, P.,Kumar, N.,Weisman, L.S.,Reinisch, K.M.
Insights into Lysosomal PI(3,5)P 2 Homeostasis from a Structural-Biochemical Analysis of the PIKfyve Lipid Kinase Complex.
Mol.Cell, 80:736-743.e4, 2020

PubMed Abstract: The phosphoinositide PI(3,5)P, generated exclusively by the PIKfyve lipid kinase complex, is key for lysosomal biology. Here, we explore how PI(3,5)P levels within cells are regulated. We find the PIKfyve complex comprises five copies of the scaffolding protein Vac14 and one copy each of the lipid kinase PIKfyve, generating PI(3,5)P from PI3P and the lipid phosphatase Fig4, reversing the reaction. Fig4 is active as a lipid phosphatase in the ternary complex, whereas PIKfyve within the complex cannot access membrane-incorporated phosphoinositides due to steric constraints. We find further that the phosphoinositide-directed activities of both PIKfyve and Fig4 are regulated by protein-directed activities within the complex. PIKfyve autophosphorylation represses its lipid kinase activity and stimulates Fig4 lipid phosphatase activity. Further, Fig4 is also a protein phosphatase acting on PIKfyve to stimulate its lipid kinase activity, explaining why catalytically active Fig4 is required for maximal PI(3,5)P production by PIKfyve in vivo.

PubMed: 33098764
DOI: 10.1016/j.molcel.2020.10.003

Experimental method

ELECTRON MICROSCOPY (5.1 Å)