PROSITE documentation PDOC50275

Sac phosphatase domain profile

The Sac domain is a region of homology between the N-terminus of synaptojanin and the otherwise unrelated yeast protein Sac1p. The Sac domain is approximately 400 residues in length, and proteins containing this domain show approximately 35% identity with other Sac domains throughout this region. The Sac domain exhibits phosphatidylinositol polyphosphate phosphatase activity and can hydrolyse phosphate from any of the three positions of inositol that may be phosphorylated (3-, 4- and 5). However, adjacent phosphates are resistant to hydrolysis. Sac domains cannot hydrolyse phosphate from phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2), or PtdIns(3,4)P2, or PtdIns(3,4,5)P3, but can hydrolyse PtdIns(3,5)P2 [1,2].

The Sac domain consists of seven highly conserved motifs which appear to define the catalytic and regulatory regions of the phosphatase. The sixth conserved region contains a highly conserved C-x(5)-R-[TS] motif, thought to be the catalytic motif of many metal-independent protein and inositide polyphosphate phosphatases. Interestingly, the Inp51p Sac domain in which the cysteine, arginine and threonine/serine residues within the C-x(5)-R-[TS] motif are absent, does not exhibit any phosphatase activity [1,2].

Two classes of Sac domain proteins have been identified in mammals as well as lower eukaryotes [1,2]. The first comprises proteins, which, in addition to an N-terminal phosphatase Sac domain, have all the domains associated with type II phosphatidylinositol phosphate 5-phosphatases:

• Mammalian synaptojanins, type II phosphatidylinositol phosphate 5- phosphatases.
• Yeast INP51, a 108 kDa membrane protein. It is involved in endocytosis and regulation of the actin cytoskeleton under conditions of normal vegetative growth. Although the Sac phosphatase domain of INP51 may be catalytically inactive, the domain may retain other functions.
• Yeast INP52, a 133 kDa membrane protein. It is involved in endocytosis and regulation of the actin cytoskeleton under conditions of normal vegetative growth.
• Yeast INP53, a 124 kDa membrane protein. It appears to have a role in intra-Golgi and Golgi-to-endosomal trafficking.

The other class of Sac-containing phosphatases consists of proteins with an N-terminal Sac phosphatase domain and no other recognizable domains:

• Yeast Sac1p, a 67 kDa membrane protein found in the endoplasmic reticulum (ER) and Golgi. It regulates the actin cytoskeleton and phospholipid metabolism.
• Yeast FIG4, a 101 kDa protein encoded by a pheromone regulated or induced gene. FIG4 might function to regulate effector molecules of the actin cytoskeleton during mating.

The profile we developed covers the seven highly conserved motifs found in Sac domains.