Phosphatase Subfamily ACP5

Phosphatase Classification: Fold PPPL: Superfamily PPPL: Family PAP: ACP5

ACP5 is found in most eukaryotes. It removes the mannose-6-phosphate trafficking signal in lysosomal proteins and is also a secreted protein phosphatase acting on osteopontin and other secreted proteins.

Evolution

ACP5 is present in some prokaryotes, and most eukaryotes, though absent from many fungi, which lack mannose-6-phosphate lysosomal targetting [1]. The single human member, ACP5 is also called tartrate resistant acid phosphatase (TRAP) or uteroferrin. Fruit fly has a single ACP5 gene (CG1637), which encodes at least five protein isoforms. C. elegans, Nematostella, sponge, Monosiga and Dictyostelium have multiple ACP5 genes; some are chromosomal neighbors, indicating recent duplication.

One Monosiga ACP5 (Phosphatase_Sequence_MbreP089_AA) has an additional SapB (Sphingolipid Activator Protein, B) domain. The unusual domain combination is also found in Salpingoeca rosetta, Capsaspora owczarzaki and Thecamonas trahens, suggesting it probably emerged in the common ancestor between Apusomonadida and Opisthokonta. The human SapB, produced by the cleavage of human PSAP gene activates many enzymes through interaction with the substrates.

Another Monosiga ACP5 (Phosphatase_Sequence_MbreP088_AA) has an additional GBP (Guanylate-binding protein) domain; One Nematostella ACP5 has two tandem phosphatase domains. Neither of these domain combinations are conserved, and may be gene prediction artefacts.

Domain

ACP5 has a purple acid phosphatase N-terminal domain, a phosphatase domain, and purple acid phosphatase C-terminal domain. The boundary of the phosphatase domain is defined according to the crystal structures [2, 3].

Functions

ACP5 dephosphorylates mannose 6-phosphate (M6P) modification on lysosomal proteins. Most newly synthesized lysosomal proteins are labelled with M6P by a Golgi-resisdent phosphotransferase. This modification is recognized by receptors that target the lysosomal proteins to the lysosome where, in most cell types, the M6P recognition marker is rapidly removed [4]. This function is shared by the unrelated phosphatase ACP2. The loss of the ACP5 subfamily in yeast may parallel their lack of M6P-based sorting [1], though plants are also believed to lack M6P sorting, yet have ACP5 members.

Human ACP5 also acts as an osteopontin phosphatase [5]. Osteopontin is an extracellular phosphoprotein involved in biomineralization and bone remodeling, as well as immune functions in heart, chemotaxis, cell activation, apoptosis. It is phosphorylated by the Golgi-resident kinase, FAM20. ACP5 modulates the ability of osteopontin to cause osteoclast migration [6] ACP5 is also secreted and may have roles in dendritic cell and macrophage activation [7, 8], fetal erythropoesis [9] and adipogenesis [10]. Other reported ACP substrates include osteonectin, bone sialoprotein, gastrin, and casein[11].

References

1. Li SC and Kane PM. The yeast lysosome-like vacuole: endpoint and crossroads. Biochim Biophys Acta. 2009 Apr;1793(4):650-63. DOI:10.1016/j.bbamcr.2008.08.003 |
2. Uppenberg J, Lindqvist F, Svensson C, Ek-Rylander B, and Andersson G. Crystal structure of a mammalian purple acid phosphatase. J Mol Biol. 1999 Jul 2;290(1):201-11. DOI:10.1006/jmbi.1999.2896 |
3. Guddat LW, McAlpine AS, Hume D, Hamilton S, de Jersey J, and Martin JL. Crystal structure of mammalian purple acid phosphatase. Structure. 1999 Jul 15;7(7):757-67. DOI:10.1016/s0969-2126(99)80100-2 |
4. Sun P, Sleat DE, Lecocq M, Hayman AR, Jadot M, and Lobel P. Acid phosphatase 5 is responsible for removing the mannose 6-phosphate recognition marker from lysosomal proteins. Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16590-5. DOI:10.1073/pnas.0807472105 |
5. Andersson G, Ek-Rylander B, Hollberg K, Ljusberg-Sjölander J, Lång P, Norgård M, Wang Y, and Zhang SJ. TRACP as an osteopontin phosphatase. J Bone Miner Res. 2003 Oct;18(10):1912-5. DOI:10.1359/jbmr.2003.18.10.1912 |
6. Ek-Rylander B and Andersson G. Osteoclast migration on phosphorylated osteopontin is regulated by endogenous tartrate-resistant acid phosphatase. Exp Cell Res. 2010 Feb 1;316(3):443-51. DOI:10.1016/j.yexcr.2009.10.019 |
7. Esfandiari E, Bailey M, Stokes CR, Cox TM, Evans MJ, and Hayman AR. TRACP Influences Th1 pathways by affecting dendritic cell function. J Bone Miner Res. 2006 Sep;21(9):1367-76. DOI:10.1359/jbmr.060611 |
8. Räisänen SR, Alatalo SL, Ylipahkala H, Halleen JM, Cassady AI, Hume DA, and Väänänen HK. Macrophages overexpressing tartrate-resistant acid phosphatase show altered profile of free radical production and enhanced capacity of bacterial killing. Biochem Biophys Res Commun. 2005 May 27;331(1):120-6. DOI:10.1016/j.bbrc.2005.03.133 |
9. Ying W, Wang H, Bazer FW, and Zhou B. Pregnancy-secreted Acid phosphatase, uteroferrin, enhances fetal erythropoiesis. Endocrinology. 2014 Nov;155(11):4521-30. DOI:10.1210/en.2014-1397 |
10. Lång P, van Harmelen V, Rydén M, Kaaman M, Parini P, Carneheim C, Cassady AI, Hume DA, Andersson G, and Arner P. Monomeric tartrate resistant acid phosphatase induces insulin sensitive obesity. PLoS One. 2008 Mar 5;3(3):e1713. DOI:10.1371/journal.pone.0001713 |
11. Andersson G and Ek-Rylander B. The tartrate-resistant purple acid phosphatase of bone osteoclasts--a protein phosphatase with multivalent substrate specificity and regulation. Acta Orthop Scand Suppl. 1995 Oct;266:189-94.