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J Biol Chem, Vol. 275, Issue 2, 801-808, January 14, 2000
From the The yeast protein Sac1p is involved in a range of
cellular functions, including inositol metabolism, actin
cytoskeletal organization, endoplasmic reticulum ATP
transport, phosphatidylinositol-phosphatidylcholine transfer protein
function, and multiple-drug sensitivity. The activity of Sac1p and its
relationship to these phenotypes are unresolved. We show here that the
regulation of lipid phosphoinositides in sac1 mutants is
defective, resulting in altered levels of all lipid phos-
phoinositides, particularly phosphatidylinositol 4-phosphate and
phosphatidylinositol 4,5-bisphosphate. We have identified two proteins
with homology to Sac1p that can suppress drug sensitivity and also
restore the levels of the phosphoinositides in sac1
mutants. Overexpression of truncated forms of these suppressor genes
confirmed that suppression was due to phosphoinositide phosphatase
activity within these proteins. We have now demonstrated this activity for Sac1p and have characterized its specificity. The in
vitro phosphatase activity and specificity of Sac1p were not
altered by some mutations. Indeed, in vivo mutant Sac1p
phosphatase activity also appeared unchanged under conditions in which
cells were drug-resistant. However, under different growth conditions,
both drug sensitivity and the phosphatase defect were manifest. It is
concluded that SAC1 encodes a novel lipid phosphoinositide
phosphatase in which specific mutations can cause the sac1
phenotypes by altering the in vivo regulation of the
protein rather than by destroying phosphatase activity.
SAC1 Encodes a Regulated Lipid Phosphoinositide
Phosphatase, Defects in Which Can Be Suppressed by the Homologous
Inp52p and Inp53p Phosphatases*
§,,
,,§§, and
Protein Phosphorylation and
Structural Biology Laboratories, Imperial Cancer Research
Fund, 44 Lincoln's Inn Fields, London WC2A 3PX, the
¶ Department of Biochemistry, Imperial College of Science,
Technology, and Medicine, Imperial College Road, London SW7 2AY, the
** Department of Anatomy, Medical School, University of Birmingham,
Birmingham B15-2TT, and the §§ Department of
Crystallography, Birkbeck College, Malet Street,
London WC1E 7HX, United Kingdom
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Recipient of a Medical Research Council fellowship.
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