Phosphatase Subfamily Laforin

Phosphatase Classification: Fold CC1: Superfamily CC1: Family DSP: Subfamily Laforin

Laforin is a glucan phosphatase and an adaptor protein.

Evolution

Laforin found in vertebrates, ciliates, alveolates and plants as well as a few scattered additional species including the animals Trichinella (nematode), Branchiostoma (lancelet) and Nematostella (anemone). It has a single human member, EPM2A.

Domain

Laforin typically has an N-terminal CBM20 carbohydrate-binding module and a C-terminal phosphatase domain. The carbohydrate-binding module targets laforin to Lafora inclusion bodies [1, 2]. The phosphatase domain directly dephosphorylates glycogen [3, 4]. Multiple plant homologs lack the CBM20 domain. Epilepsy-caused mutations are found on both domains.

Function

Laforin is a glucan phosphatase [3, 4] and a phosphatase of muscle glycogen synthase (GS1) in polyglucosan bodies (PBs). In Lafora disease (LD), the deficiency of either laforin or the E3 ligase malin causes massive accumulation of less-branched glycogen inclusions, known as Lafora bodies, also called polyglucosan bodies (PBs), in several types of cells including neurons. Once GS1-synthesized polyglucosan accumulates into PBs, laforin recruits malin to the PBs where laforin dephosphorylates, and malin degrades the GS1 in concert with GPBB and AGL1, resulting in a breakdown of polyglucosan [5].

Laforin also dephosphorylates Ser 9 of Glycogen synthase kinase 3 [6].

Laforin also serves as an adaptor protein involved in several physiological pathways [7]. For instance, the complex of laforin and malin modules protein phosphatase 1 regulatory subunit PPP1R3D via ubiquitination [8]. See [7] for details.

DSP4/SEX4 is one of several plant Laforins, and is implicated in breakdown of starch in the chloroplast [9], as is another family member, LSF2 [10], while LSF1 is predicted to be an inactive scaffold [11]

References

1. Wang J, Stuckey JA, Wishart MJ, and Dixon JE. A unique carbohydrate binding domain targets the lafora disease phosphatase to glycogen. J Biol Chem. 2002 Jan 25;277(4):2377-80. DOI:10.1074/jbc.C100686200 |
2. Ganesh S, Tsurutani N, Suzuki T, Hoshii Y, Ishihara T, Delgado-Escueta AV, and Yamakawa K. The carbohydrate-binding domain of Lafora disease protein targets Lafora polyglucosan bodies. Biochem Biophys Res Commun. 2004 Jan 23;313(4):1101-9. DOI:10.1016/j.bbrc.2003.12.043 |
3. Worby CA, Gentry MS, and Dixon JE. Laforin, a dual specificity phosphatase that dephosphorylates complex carbohydrates. J Biol Chem. 2006 Oct 13;281(41):30412-8. DOI:10.1074/jbc.M606117200 |
4. Gentry MS, Dowen RH 3rd, Worby CA, Mattoo S, Ecker JR, and Dixon JE. The phosphatase laforin crosses evolutionary boundaries and links carbohydrate metabolism to neuronal disease. J Cell Biol. 2007 Jul 30;178(3):477-88. DOI:10.1083/jcb.200704094 |
5. Liu Y, Zeng L, Ma K, Baba O, Zheng P, Liu Y, and Wang Y. Laforin-malin complex degrades polyglucosan bodies in concert with glycogen debranching enzyme and brain isoform glycogen phosphorylase. Mol Neurobiol. 2014 Apr;49(2):645-57. DOI:10.1007/s12035-013-8546-z |
6. Lohi H, Ianzano L, Zhao XC, Chan EM, Turnbull J, Scherer SW, Ackerley CA, and Minassian BA. Novel glycogen synthase kinase 3 and ubiquitination pathways in progressive myoclonus epilepsy. Hum Mol Genet. 2005 Sep 15;14(18):2727-36. DOI:10.1093/hmg/ddi306 |
7. Gentry MS, Romá-Mateo C, and Sanz P. Laforin, a protein with many faces: glucan phosphatase, adapter protein, et alii. FEBS J. 2013 Jan;280(2):525-37. DOI:10.1111/j.1742-4658.2012.08549.x |
8. Rubio-Villena C, Garcia-Gimeno MA, and Sanz P. Glycogenic activity of R6, a protein phosphatase 1 regulatory subunit, is modulated by the laforin-malin complex. Int J Biochem Cell Biol. 2013 Jul;45(7):1479-88. DOI:10.1016/j.biocel.2013.04.019 |
9. Kötting O, Santelia D, Edner C, Eicke S, Marthaler T, Gentry MS, Comparot-Moss S, Chen J, Smith AM, Steup M, Ritte G, and Zeeman SC. STARCH-EXCESS4 is a laforin-like Phosphoglucan phosphatase required for starch degradation in Arabidopsis thaliana. Plant Cell. 2009 Jan;21(1):334-46. DOI:10.1105/tpc.108.064360 |
10. Santelia D, Kötting O, Seung D, Schubert M, Thalmann M, Bischof S, Meekins DA, Lutz A, Patron N, Gentry MS, Allain FH, and Zeeman SC. The phosphoglucan phosphatase like sex Four2 dephosphorylates starch at the C3-position in Arabidopsis. Plant Cell. 2011 Nov;23(11):4096-111. DOI:10.1105/tpc.111.092155 |
11. Silver DM, Kötting O, and Moorhead GB. Phosphoglucan phosphatase function sheds light on starch degradation. Trends Plant Sci. 2014 Jul;19(7):471-8. DOI:10.1016/j.tplants.2014.01.008 |
12. Liu Y, Wang Y, Wu C, Liu Y, and Zheng P. Dimerization of Laforin is required for its optimal phosphatase activity, regulation of GSK3beta phosphorylation, and Wnt signaling. J Biol Chem. 2006 Nov 17;281(46):34768-74. DOI:10.1074/jbc.M607778200 |