The phosphatase laforin crosses evolutionary boundaries and links carbohydrate metabolism to neuronal disease

Gentry, Matthew S.; Dowen, Robert H.; Worby, Carolyn A.; Mattoo, Seema; Ecker, Joseph R.; Dixon, Jack E.

doi:10.1084/jem2048oia22

Cited by 44 publications

(163 citation statements)

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“…Although it was originally described as a dualspecificity protein phosphatase (PTPKIS1; FordhamSkelton et al, 2002;Kerk et al, 2006), we have shown that the function of the SEX4 phosphatase is to remove phosphate groups added to starch by GWD (and perhaps PWD), thus facilitating the complete degradation of oligosaccharides by b-amylase (Kö tting et al, 2009). Recombinant SEX4 catalyzes the dephosphorylation of glucans, including starch polymers, glycogen, soluble oligosaccharides, and leaf starch granules (Gentry et al, 2007). sex4 mutant plants have greatly elevated levels of phosphorylated malto-oligosaccharides (Kötting et al, 2009).…”

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confidence: 79%

“…Although some of these proteins dephosphorylate proteins in vivo, others do not. SEX4 and the related animal glycogen phosphatase laforin (Gentry et al, 2007) are examples with nonprotein substrates; others include the lipid phosphatase PTEN (phosphatase and tensin homolog) that dephosphorylates phosphatidylinositol-3,4,5-triphosphate and thus acts as a suppressor of the phosphoinositide 3-kinase signaling pathway implicated in several mammalian cancers (Maehama and Dixon, 1998). At present, sequence inspection does not allow the substrate specificity of these enzymes to be predicted.…”

Section: Possible Function Of Lsf1mentioning

confidence: 99%

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A Putative Phosphatase, LSF1, Is Required for Normal Starch Turnover in Arabidopsis Leaves

et al. 2009

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A putative phosphatase, LSF1 (for LIKE SEX4; previously PTPKIS2), is closely related in sequence and structure to STARCH-EXCESS4 (SEX4), an enzyme necessary for the removal of phosphate groups from starch polymers during starch degradation in Arabidopsis (Arabidopsis thaliana) leaves at night. We show that LSF1 is also required for starch degradation: lsf1 mutants, like sex4 mutants, have substantially more starch in their leaves than wild-type plants throughout the diurnal cycle. LSF1 is chloroplastic and is located on the surface of starch granules. lsf1 and sex4 mutants show similar, extensive changes relative to wild-type plants in the expression of sugar-sensitive genes. However, although LSF1 and SEX4 are probably both involved in the early stages of starch degradation, we show that LSF1 neither catalyzes the same reaction as SEX4 nor mediates a sequential step in the pathway. Evidence includes the contents and metabolism of phosphorylated glucans in the single mutants. The sex4 mutant accumulates soluble phospho-oligosaccharides undetectable in wild-type plants and is deficient in a starch granuledephosphorylating activity present in wild-type plants. The lsf1 mutant displays neither of these phenotypes. The phenotype of the lsf1/sex4 double mutant also differs from that of both single mutants in several respects. We discuss the possible role of the LSF1 protein in starch degradation.

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confidence: 79%

Section: Possible Function Of Lsf1mentioning

confidence: 99%

A Putative Phosphatase, LSF1, Is Required for Normal Starch Turnover in Arabidopsis Leaves

et al. 2009

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“…SEX4 contains an amino-terminal chloroplast Targeting Peptide (cTP), followed by a dual specificity phosphatase (DSP) domain, and carbohydrate-binding module (CBM) (17,18). Mutations in the SEX4 gene result in substantial accumulations of starch in A. thaliana leaves due to decreased rates of degradation and the accumulation of soluble phospho-oligosaccharides (16,(19)(20)(21).…”

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confidence: 99%

“…Mutations in the SEX4 gene result in substantial accumulations of starch in A. thaliana leaves due to decreased rates of degradation and the accumulation of soluble phospho-oligosaccharides (16,(19)(20)(21). In addition to dephosphorylating amylopectin (18), recombinant SEX4 also dephosphorylates crystalline maltodextrins (22), starch granules isolated from A. thaliana leaves (16), and phospho-oligosaccharides (16). While C6 and C3 phosphorylation is carried out by two dikinases, SEX4 is able to dephosphorylate both C6 and C3 positions with similar kinetics (22).…”

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Structural basis for the glucan phosphatase activity of Starch Excess4

Kooi

Taylor

Pace

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Living organisms utilize carbohydrates as essential energy storage molecules. Starch is the predominant carbohydrate storage molecule in plants while glycogen is utilized in animals. Starch is a water-insoluble polymer that requires the concerted activity of kinases and phosphatases to solubilize the outer surface of the glucan and mediate starch catabolism. All known plant genomes encode the glucan phosphatase Starch Excess4 (SEX4). SEX4 can dephosphorylate both the starch granule surface and soluble phosphoglucans and is necessary for processive starch metabolism. The physical basis for the function of SEX4 as a glucan phosphatase is currently unclear. Herein, we report the crystal structure of SEX4, containing phosphatase, carbohydrate-binding, and C-terminal domains. The three domains of SEX4 fold into a compact structure with extensive interdomain interactions. The C-terminal domain of SEX4 integrally folds into the core of the phosphatase domain and is essential for its stability. The phosphatase and carbohydratebinding domains directly interact and position the phosphatase active site toward the carbohydrate-binding site in a single continuous pocket. Mutagenesis of the phosphatase domain residue F167, which forms the base of this pocket and bridges the two domains, selectively affects the ability of SEX4 to function as a glucan phosphatase. Together, these results reveal the unique tertiary architecture of SEX4 that provides the physical basis for its function as a glucan phosphatase.carbohydrate | Lafora disease | laforin | phosphorylation P lants and animals store carbohydrates as starch and glycogen, respectively. Starch is produced in diurnal cycles and is composed of <10% w∕w amylose and >80% w∕w amylopectin in Arabidopsis thaliana leaves (1). Amylose is a linear molecule composed of glucose moieties linked by α-1,4-glycosidic linkages with very few branches. Amylopectin, which is similar to glycogen, is composed of α-1,4-glycosidic linkages with α-1,6-glycosidic branches, but amylopectin branches are arranged in clusters at regular intervals and the branches form double helices that pack together to form crystalline lamellae (2, 3). The decreased branching and crystalline lamellae of amylopectin are key contributors to the insolubility of starch, while glycogen has more branches and is water-soluble.Starch is a water-insoluble polymer whose surface is inaccessible to most enzymes. Recent work convincingly demonstrates that reversible starch phosphorylation and dephosphorylation is essential for processive starch metabolism (reviewed in refs. 4-7). An essential signal triggering starch catabolism is phosphorylation on the C6 position of glucose moieties on the surface of starch by glucan water dikinase (GWD/R1) (8, 9). C6 phosphorylation triggers C3 phosphorylation by phosphoglucan water dikinase (PWD) (8,10,11). Recent data suggest that C6 phosphorylation fits within the unphosphorylated structure of the amylopectin helix, but C3 phosphorylation imposes significant steric effects and is predicted t...

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The unique evolution of the carbohydrate‐binding module CBM20 in laforin

2018

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Laforin catalyses glycogen dephosphorylation. Mutations in its gene result in Lafora disease, a fatal progressive myoclonus epilepsy, the hallmark being water-insoluble, hyperphosphorylated carbohydrate inclusions called Lafora bodies. Human laforin consists of an N-terminal carbohydrate-binding module (CBM) from family CBM20 and a C-terminal dual-specificity phosphatase domain. Laforin is conserved in all vertebrates, some basal metazoans and a small group of protozoans. The present in silico study defines the evolutionary relationships among the CBM20s of laforin with an emphasis on newly identified laforin orthologues. The study reveals putative laforin orthologues in Trichinella, a parasitic nematode, and identifies two sequence inserts in the CBM20 of laforin from parasitic coccidia. Finally, we identify that the putative laforin orthologues from some protozoa and algae possess more than one CBM20.

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The phosphatase laforin crosses evolutionary boundaries and links carbohydrate metabolism to neuronal disease

Cited by 44 publications

References 1 publication

A Putative Phosphatase, LSF1, Is Required for Normal Starch Turnover in Arabidopsis Leaves

A Putative Phosphatase, LSF1, Is Required for Normal Starch Turnover in Arabidopsis Leaves

Structural basis for the glucan phosphatase activity of Starch Excess4

The unique evolution of the carbohydrate‐binding module CBM20 in laforin

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