Phosphatase Subfamily FIG4

Phosphatase Classification: Fold CC1: Superfamily CC1: Family Sac: Subfamily FIG4 (SAC3)

FIG4 (SAC3) is a phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) phosphatase located in the vacuolar membrane. It is associated with a form of Charcot-Marie-Tooth disorder CMT4J, Yunis-Varón syndrome, and amyotrophic lateral sclerosis (ALS). FIG4 is found in most if not all eukaryotes.

Evolution

The FIG4 (SAC3) subfamily is conserved in eukaryotes. It is present in almost all the 203 eukaryotic genomes in gOrtholog database (internal).

Domain

The FIG4 (SAC3) subfamily has a single structural domain, SAC phosphatase domain.

Function

FIG4 (SAC3) is a phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) phosphatase located in the vacuolar membrane. PtdIns(3,5)P2, a low abundance PI comprising as little as 0.8% of total PIs in mammalian cells, mediates essential aspects of endocytic membrane homeostasis and coordinates fission and fusion events in the multivesicular endosomal system of mammalian cells [1]. FIG4 (SAC3) functions in the complex with PIKfyve (the sole kinase for PtdIns(3,5)P2 synthesis) and the PIKfyve activator ArPIKfyve [2, 3]. The triple PIKfyve-ArPIKfyve-Sac3 (PAS) complex ensures the PtdIns(3,5)P2 homeostatic control by rapid turnover counterbalancing locally elevated PtdIns(3,5)P2 [1]. A model of domain interactions within the PAS core and their role in regulating the enzymatic activities was summarized in Figure 6 of [1].

FIG4 (SAC3) with deleterious mutations causes neurodegeneration in patients with a form of autosomal recessive Charcot-Marie-Tooth disorder, CMT4J and in the pale tremor mouse [4, 5, 6]. It also causes Yunis-Varón syndrome [7, 8]. In addition, it is also a risk factor of amyotrophic lateral sclerosis (ALS) [9, 10].

References

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