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Human Molecular Genetics Advance Access originally published online on October 7, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 23 3161-3171
DOI: 10.1093/hmg/ddg340
© 2003 Oxford University Press

Laforin, the dual-phosphatase responsible for Lafora disease, interacts with R5 (PTG), a regulatory subunit of protein phosphatase-1 that enhances glycogen accumulation

Maria Elena Fernández-Sánchez1,{dagger}, Olga Criado-García1,{dagger}, Karen E. Heath1,{dagger},{ddagger}, Belén García-Fojeda1, Iria Medraño-Fernández1, Pilar Gomez-Garre2, Pascual Sanz3, José María Serratosa2 and Santiago Rodríguez de Córdoba1,*

1Departamento de Inmunología, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain, 2Servicio de Neurología, Fundación Jiménez Díaz, Madrid, Spain and 3Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Científicas, Valencia, Spain

Received August 22, 2003; Accepted September 30, 2003

Progressive myoclonus epilepsy of Lafora type (LD, MIM 254780) is a fatal autosomal recessive disorder characterized by the presence of progressive neurological deterioration, myoclonus, epilepsy and polyglucosan intracellular inclusion bodies, called Lafora bodies. Lafora bodies resemble glycogen with reduced branching, suggesting an alteration in glycogen metabolism. Linkage analysis and homozygosity mapping localized EPM2A, a major gene for LD, to chromosome 6q24. EPM2A encodes a protein of 331 amino acids (named laforin) with two domains, a dual-specificity phosphatase domain and a carbohydrate binding domain. Here we show that, in addition, laforin interacts with itself and with the glycogen targeting regulatory subunit R5 of protein phosphatase 1 (PP1). R5 is the human homolog of the murine Protein Targeting to Glycogen, a protein that also acts as a molecular scaffold assembling PP1 with its substrate, glycogen synthase, at the intracellular glycogen particles. The laforin–R5 interaction was confirmed by pull-down and co-localization experiments. Full-length laforin is required for the interaction. However, a minimal central region of R5 (amino acids 116–238), including the binding sites for glycogen and for glycogen synthase, is sufficient to interact with laforin. Point-mutagenesis of the glycogen synthase-binding site completely blocked the interaction with laforin. The majority of the EPM2A missense mutations found in LD patients result in lack of phosphatase activity, absence of binding to glycogen and lack of interaction with R5. Interestingly, we have found that the LD-associated EPM2A missense mutation G240S has no effect on the phosphatase or glycogen binding activities of laforin but disrupts the interaction with R5, suggesting that binding to R5 is critical for the laforin function. These results place laforin in the context of a multiprotein complex associated with intracellular glycogen particles, reinforcing the concept that laforin is involved in the regulation of glycogen metabolism.

* To whom correspondence should be addressed at: Departamento de Inmunología, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, 28040 Madrid, Spain. Tel: +34 918373112; Fax: +34 915340432; Email: srdecordoba{at}cib.csic.es

{dagger} The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.

{ddagger} Present address:

Departamento de Pediatria, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.


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