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

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dc.contributor.authorFernández-Sánchez, M. E.
dc.contributor.authorCriado-García, O.
dc.contributor.authorHeath, K. E.
dc.contributor.authorGarcía-Fojeda García-Valdecasas, María Belén
dc.contributor.authorMedraño-Fernández, Iria
dc.contributor.authorGómez-Garre, Pilar
dc.contributor.authorSanz, Pascual
dc.contributor.authorSerratosa, José María
dc.contributor.authorRodríguez de Córdoba, Santiago
dc.date.accessioned2024-02-02T12:34:40Z
dc.date.available2024-02-02T12:34:40Z
dc.date.issued2003-09-30
dc.description.abstractProgressive 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.
dc.description.departmentDepto. de Bioquímica y Biología Molecular
dc.description.facultyFac. de Ciencias Químicas
dc.description.refereedTRUE
dc.description.sponsorshipMinisterio de Ciencia y Tecnología
dc.description.sponsorshipInstituto de Salud Carlos III
dc.description.sponsorshipAsociación Lafora España
dc.description.statuspub
dc.identifier.citationMaria Elena Fernández-Sánchez, Olga Criado-García, Karen E. Heath, Belén García-Fojeda, Iria Medraño-Fernández, Pilar Gomez-Garre, Pascual Sanz, José María Serratosa, Santiago Rodríguez de Córdoba, Laforin, the dual-phosphatase responsible for Lafora disease, interacts with R5 (PTG), a regulatory subunit of protein phosphatase-1 that enhances glycogen accumulation, Human Molecular Genetics, Volume 12, Issue 23, 1 December 2003, Pages 3161–3171, https://doi.org/10.1093/hmg/ddg340
dc.identifier.doi10.1093/hmg/ddg340
dc.identifier.issn1460-2083
dc.identifier.officialurlhttps://academic.oup.com/hmg/article/12/23/3161/692482
dc.identifier.relatedurlhttps://pubmed.ncbi.nlm.nih.gov/14532330/
dc.identifier.urihttps://hdl.handle.net/20.500.14352/98262
dc.issue.number23
dc.journal.titleHuman Molecular Genetics
dc.language.isoeng
dc.page.final3171
dc.page.initial3161
dc.publisherOxford University Press
dc.relation.projectIDSAF2001- 0613
dc.relation.projectIDPI02/0536
dc.relation.projectIDG03/054
dc.relation.projectIDG03/011
dc.rightsAttribution-NonCommercial 4.0 Internationalen
dc.rights.accessRightsopen access
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/
dc.subject.cdu577.1
dc.subject.cdu577.2
dc.subject.cdu575
dc.subject.keywordMutation
dc.subject.keywordAmino acids
dc.subject.keywordGlycogen
dc.subject.keywordGlycogen (starch) synthase
dc.subject.keywordLafora disease
dc.subject.keywordProtein phosphatase
dc.subject.keywordPhosphoric monoester hydrolases
dc.subject.keywordYeasts
dc.subject.keywordMice
dc.subject.ucmBioquímica (Biología)
dc.subject.ucmGenética
dc.subject.ucmBiología molecular (Biología)
dc.subject.unesco2403 Bioquímica
dc.subject.unesco2415 Biología Molecular
dc.subject.unesco2409 Genética
dc.titleLaforin, the dual-phosphatase responsible for Lafora disease, interacts with R5 (PTG), a regulatory subunit of protein phosphatase-1 that enhances glycogen accumulation
dc.typejournal article
dc.type.hasVersionVoR
dc.volume.number12
dspace.entity.typePublication
relation.isAuthorOfPublication89ed03ac-f011-4290-9a31-7390e12f1724
relation.isAuthorOfPublication.latestForDiscovery89ed03ac-f011-4290-9a31-7390e12f1724
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