Phosphatase Subfamily SAC1

Phosphatase Classification: Fold CC1: Superfamily CC1: Family Sac: Subfamily SAC1

SAC1 is an integral membrane phosphoinositide phosphatase located in endoplasmic reticulum (ER) and golgi apparatus. SAC1 is conserved in eukaryotes.

Evolution

The SAC1 subfamily is conserved in eukaryotes. It is present in almost all the 203 eukaryotic genomes in gOrtholog database (internal).

Domain

The SAC1 subfamily has SAC phosphatase domain.

Human SAC1 has a C-terminal tail of ~90 amino acid. The C-terminal tail a dual-pass transmembrane region. Human SAC1 also has a KxKxx motif of the last five C-terminal residues which mediates its interaction with COPI complex [1]. The motif is not strictly conserved, and it is unclear whether the last C-terminal residues of yeast SAC1 interacts with COPI complex.

Human SAC1 has a RLNSTSP motif (145-151) interacting with 14-3-3, which binds to COPII complex and serves as a cytosolic adaptor in mediating SAC1 transport in COPII-coated vesicle [2]. The motif within the phosphatase domain is not conserved among SAC1s. An alignment of SAC1s in phosphatome.net shows none of the seven residues are strictly conserved.

Function

The members of the SAC1 subfamily are integral membrane phosphoinositide phosphatases that play evolutionary conserved roles in eukaryotic cell physiology [3]. It locates in the endoplasmic reticulum (ER) and the Golgi apparatus in yeast [4] and mammals [1].

SAC1 is best characterized in Saccharomyces cerevisiae [5, 6]. 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. Sac1p is able to dephosphorylate PtdIns[3]P, PtdIns[4]P, and PtdIns[3,5]P2 in vitro, the role of Sac1p in processes involving PtdIns[4]P has been the primary focus of in vivo studies (see SGD).

In mammals, it regulates Golgi membrane morphology and mitotic spindle organization [7]. The human SAC1 is widely expressed in different tissues (see GTEx). It interacts with the coatomer I complex via a putative COPI interaction motif (KXKXX) at its C terminus in a manner dependent on its catalytic activity [1].

References

1. Rohde HM, Cheong FY, Konrad G, Paiha K, Mayinger P, and Boehmelt G. The human phosphatidylinositol phosphatase SAC1 interacts with the coatomer I complex. J Biol Chem. 2003 Dec 26;278(52):52689-99. DOI:10.1074/jbc.M307983200 |
2. Bajaj Pahuja K, Wang J, Blagoveshchenskaya A, Lim L, Madhusudhan MS, Mayinger P, and Schekman R. Phosphoregulatory protein 14-3-3 facilitates SAC1 transport from the endoplasmic reticulum. Proc Natl Acad Sci U S A. 2015 Jun 23;112(25):E3199-206. DOI:10.1073/pnas.1509119112 |
3. Nemoto Y, Kearns BG, Wenk MR, Chen H, Mori K, Alb JG Jr, De Camilli P, and Bankaitis VA. Functional characterization of a mammalian Sac1 and mutants exhibiting substrate-specific defects in phosphoinositide phosphatase activity. J Biol Chem. 2000 Nov 3;275(44):34293-305. DOI:10.1074/jbc.M003923200 |
4. Konrad G, Schlecker T, Faulhammer F, and Mayinger P. Retention of the yeast Sac1p phosphatase in the endoplasmic reticulum causes distinct changes in cellular phosphoinositide levels and stimulates microsomal ATP transport. J Biol Chem. 2002 Mar 22;277(12):10547-54. DOI:10.1074/jbc.M200090200 |
5. Cleves AE, Novick PJ, and Bankaitis VA. Mutations in the SAC1 gene suppress defects in yeast Golgi and yeast actin function. J Cell Biol. 1989 Dec;109(6 Pt 1):2939-50. DOI:10.1083/jcb.109.6.2939 |
6. Cai Y, Deng Y, Horenkamp F, Reinisch KM, and Burd CG. Sac1-Vps74 structure reveals a mechanism to terminate phosphoinositide signaling in the Golgi apparatus. J Cell Biol. 2014 Aug 18;206(4):485-91. DOI:10.1083/jcb.201404041 |
7. Liu Y, Boukhelifa M, Tribble E, Morin-Kensicki E, Uetrecht A, Bear JE, and Bankaitis VA. The Sac1 phosphoinositide phosphatase regulates Golgi membrane morphology and mitotic spindle organization in mammals. Mol Biol Cell. 2008 Jul;19(7):3080-96. DOI:10.1091/mbc.e07-12-1290 |