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J. Biol. Chem., Vol. 278, Issue 52, 52689-52699, December 26, 2003

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The Human Phosphatidylinositol Phosphatase SAC1 Interacts with the Coatomer I Complex^*

Holger M. Rohde, Fei Ying Cheong¶, Gerlinde Konrad, Karin Paiha||, Peter Mayinger**, and Guido Boehmelt

From the Boehringer Ingelheim Austria GmbH, Dr. Boehringer-Gasse 5-11, 1121 Vienna, Austria, Zentrum für Molekulare Biologie, Universität Heidelberg, Im Neuenheimer Feld 282, D-69120 Heidelberg, Germany, ^||Research Institute of Molecular Pathology, Dr. Bohr-Gasse 7, 1030 Vienna, Austria

The Saccharomyces cerevisiae SAC1 gene encodes an integral membrane protein of the endoplasmic reticulum (ER) and the Golgi apparatus. Yeast SAC1 mutants display a wide array of phenotypes including inositol auxotrophy, cold sensitivity, secretory defects, disturbed ATP transport into the ER, or suppression of actin gene mutations. At present, it is not clear how these phenotypes relate to the finding that SAC1 displays polyphosphoinositide phosphatase activity. Moreover, it is still an open question whether SAC1 functions similarly in mammalian cells, since some phenotypes are yeast-specific. Potential protein interaction partners and, connected to that, possible regulatory circuits have not been described. Therefore, we have cloned human SAC1 (hSAC1), show that it behaves similar to ySac1p in terms of substrate specificity, demonstrate that the endogenous protein localizes to the ER and Golgi, and identify for the first time members of the coatomer I (COPI) complex as interaction partners of hSAC1. Mutation of a putative COPI interaction motif (KXKXX) at its C terminus abolishes interaction with COPI and causes accumulation of hSAC1 in the Golgi. In addition, we generated a catalytically inactive mutant, demonstrate that its lipid binding capacity is unaltered, and show that it accumulates in the Golgi, incapable of interacting with the COPI complex despite the presence of the KXKXX motif. These results open the possibility that the enzymatic function of hSAC1 provides a switch for accessibility of the COPI interaction motif.

Received for publication, July 22, 2003 , and in revised form, October 1, 2003.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AB020658.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Supported by a stipend from the Deutsche Forschungsgemeinschaft (GRK 230). Present address: Division of Nephrology and Hypertension, Oregon Health and Science University, Portland, OR 97239.

^** Supported by Deutsche Forschungsgemeinschaft Grant Ma 1363/5-2. Present address: Division of Nephrology and Hypertension, Oregon Health and Science University, Portland, OR 97239.

To whom correspondence should be addressed. Tel.: 43-1-80105-2667; Fax: 43-1-80105-2782; E-mail: guido.boehmelt{at}vie.boehringeringelheim.com.

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