title: Sac1-Vps74 structure reveals a mechanism to terminate phosphoinositide signaling in the Golgi apparatus.
abstract: 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.
authors.affiliation: Department of Cell Biology, Yale School of Medicine, New Haven, CT 06520.
authors.forename: Yiying
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Department of Cell Biology, Yale School of Medicine, New Haven, CT 06520.
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Department of Cell Biology, Yale School of Medicine, New Haven, CT 06520.
authors.forename: Florian
authors.initials: F
authors.lastname: Horenkamp
authors.affiliation: Department of Cell Biology, Yale School of Medicine, New Haven, CT 06520 christopher.burd@yale.edu karin.reinisch@yale.edu.
authors.forename: Karin M
authors.initials: KM
authors.lastname: Reinisch
authors.affiliation: Department of Cell Biology, Yale School of Medicine, New Haven, CT 06520 christopher.burd@yale.edu karin.reinisch@yale.edu.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Burd
mesh_terms: D002352:Carrier Proteins / Q000648:ultrastructure*; D002384:Catalysis; D018360:Crystallography, X-Ray; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism*; D049452:Green Fluorescent Proteins; D008565:Membrane Proteins / Q000378:metabolism / Q000648:ultrastructure; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000648:ultrastructure*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000648:ultrastructure*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000648:ultrastructure*
chemical_list: D002352:Carrier Proteins; C429024:GOLPH3 protein, human; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D018129:Phosphatidylinositol Phosphates; D029701:Saccharomyces cerevisiae Proteins; C528905:Vps74 protein, S cerevisiae; C037178:phosphatidylinositol 4-phosphate; D049452:Green Fluorescent Proteins; C081864:SAC1 protein, S cerevisiae; D010744:Phosphoric Monoester Hydrolases
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