title: Crystal structure of the yeast Sac1: implications for its phosphoinositide phosphatase function.
abstract: Sac family phosphoinositide (PI) phosphatases are an essential family of CX(5)R(T/S)-based enzymes, involved in numerous aspects of cellular function such as PI homeostasis, cellular signalling, and membrane trafficking. Genetic deletions of several Sac family members result in lethality in animal models and mutations of the Sac3 gene have been found in human hereditary diseases. In this study, we report the crystal structure of a founding member of this family, the Sac phosphatase domain of yeast Sac1. The 2.0 A resolution structure shows that the Sac domain comprises of two closely packed sub-domains, a novel N-terminal sub-domain and the PI phosphatase catalytic sub-domain. The structure further shows a striking conformation of the catalytic P-loop and a large positively charged groove at the catalytic site. These findings suggest an unusual mechanism for its dephosphorylation function. Homology structural modeling of human Fig4/Sac3 allows the mapping of several disease-related mutations and provides a framework for the understanding of the molecular mechanisms of human diseases.
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Manford
authors.forename: Tian
authors.initials: T
authors.lastname: Xia
authors.forename: Ajay Kumar
authors.initials: AK
authors.lastname: Saxena
authors.forename: Christopher
authors.initials: C
authors.lastname: Stefan
authors.forename: Fenghua
authors.initials: F
authors.lastname: Hu
authors.forename: Scott D
authors.initials: SD
authors.lastname: Emr
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Mao
mesh_terms: D000595:Amino Acid Sequence; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D005420:Flavoproteins / Q000737:chemistry / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D017510:Protein Folding; D012441:Saccharomyces cerevisiae / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D040681:Structural Homology, Protein
chemical_list: D005420:Flavoproteins; D029701:Saccharomyces cerevisiae Proteins; C522215:FIG4 protein, human; C081864:SAC1 protein, S cerevisiae; D010744:Phosphoric Monoester Hydrolases
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