Sac1-Vps74 structure reveals a mechanism to terminate phosphoinositide signaling in the Golgi apparatus.
Publication Type:
Journal ArticleSource:
J Cell Biol, Volume 206, Issue 4, p.485-91 (2014)Keywords:
Carrier Proteins, Catalysis, Crystallography, X-Ray, Endoplasmic Reticulum, Golgi Apparatus, Green Fluorescent Proteins, Membrane Proteins, Models, Molecular, Multiprotein Complexes, Phosphatidylinositol Phosphates, Phosphoric Monoester Hydrolases, Protein Binding, Protein Structure, Tertiary, Saccharomyces cerevisiae, Saccharomyces cerevisiae ProteinsAbstract:
<p>Sac1 is a phosphoinositide phosphatase of the endoplasmic reticulum and Golgi apparatus that controls organelle membrane composition principally via regulation of phosphatidylinositol 4-phosphate signaling. We present a characterization of the structure of the N-terminal portion of yeast Sac1, containing the conserved Sac1 homology domain, in complex with Vps74, a phosphatidylinositol 4-kinase effector and the orthologue of human GOLPH3. The interface involves the N-terminal subdomain of the Sac1 homology domain, within which mutations in the related Sac3/Fig4 phosphatase have been linked to Charcot-Marie-Tooth disorder CMT4J and amyotrophic lateral sclerosis. Disruption of the Sac1-Vps74 interface results in a broader distribution of phosphatidylinositol 4-phosphate within the Golgi apparatus and failure to maintain residence of a medial Golgi mannosyltransferase. The analysis prompts a revision of the membrane-docking mechanism for GOLPH3 family proteins and reveals how an effector of phosphoinositide signaling serves a dual function in signal termination. </p>