Phosphatase Subfamily Laforin

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

Laforin is a subfamily found in vertebrates and scattered among other species. It's not only a phosphatase, but also acts as an adaptor protein involved in different physiological pathways.

Evolution

Laforin found in vertebrates, ciliates, alveolates and plants as well as a few 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].

laforin is also a phosphatase of muscle glycogen synthase (GS1) in polyglucosan bodies (PBs). In Lafora disease (LD), the deficiency of either laforin or 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 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.

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. 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 |