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J. Biol. Chem., Vol. 281, Issue 41, 30412-30418, October 13, 2006
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Laforin, a Dual Specificity Phosphatase That Dephosphorylates Complex Carbohydrates*
From the Departments of Pharmacology, Cellular and Molecular Medicine, and Chemistry and Biochemistry, University of California at San Diego, La Jolla, California 92093-0721
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.
Received for publication, June 26, 2006 , and in revised form, August 10, 2006.
* This work was supported by NCI, National Institutes of Health (NIH), Grant T32CA09523 (to M. S. G.), NIH Grants 18024 and 18849 (to J. E. D.), and the Walther Cancer Institute (to J. E. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 To whom correspondence should be addressed: Depts. of Pharmacology, Cellular and Molecular Medicine, and Chemistry and Biochemistry, University of California at San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0721. Tel.: 858-822-0491; Fax: 858-822-5888; E-mail: jedixon{at}ucsd.edu.
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