Worby Carolyn A, Gentry Matthew S, Dixon Jack E
Department of Pharmacology, University of California at San Diego, La Jolla, California 92093-0721, USA.
J Biol Chem. 2006 Oct 13;281(41):30412-8. doi: 10.1074/jbc.M606117200. Epub 2006 Aug 10.
Laforin is the only phosphatase in the animal kingdom that contains a carbohydrate-binding module. Mutations in the gene encoding laforin result in Lafora disease, a fatal autosomal recessive neurodegenerative disorder, which is diagnosed by the presence of intracellular deposits of insoluble complex carbohydrates known as Lafora bodies. We demonstrate that laforin interacts with proteins known to be involved in glycogen metabolism and rule out several of these proteins as potential substrates. Surprisingly, we find that laforin displays robust phosphatase activity against a phosphorylated complex carbohydrate. Furthermore, this activity is unique to laforin, since several other phosphatases are unable to dephosphorylate polysaccharides. Finally, fusing the carbohydrate-binding module of laforin to the dual specific phosphatase VHR does not result in the ability of this phosphatase to dephosphorylate polysaccharides. Therefore, we hypothesize that laforin is unique in its ability to utilize a phosphorylated complex carbohydrate as a substrate and that this function may be necessary for the maintenance of normal cellular glycogen.
拉福林是动物界唯一一种含有碳水化合物结合模块的磷酸酶。编码拉福林的基因突变会导致拉福拉病，这是一种致命的常染色体隐性神经退行性疾病，通过细胞内存在称为拉福拉小体的不溶性复合碳水化合物沉积物来诊断。我们证明拉福林与已知参与糖原代谢的蛋白质相互作用，并排除了其中几种蛋白质作为潜在底物的可能性。令人惊讶的是，我们发现拉福林对磷酸化的复合碳水化合物具有强大的磷酸酶活性。此外，这种活性是拉福林所特有的，因为其他几种磷酸酶无法使多糖去磷酸化。最后，将拉福林的碳水化合物结合模块与双特异性磷酸酶VHR融合，并不会导致该磷酸酶具有使多糖去磷酸化的能力。因此，我们推测拉福林在利用磷酸化复合碳水化合物作为底物的能力方面是独特的，并且这种功能可能是维持正常细胞糖原所必需的。
