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Figure 1 | Genome Medicine

Figure 1

From: LARGE enzyme activity deciphered: a new therapeutic target for muscular dystrophies

Figure 1

Key glycans on α-dystroglycan. Dystroglycan contains unusual O-mannosyl glycans that are necessary for ligand binding activity. (a) Two structures that have been implicated in ligand binding by genetic and biochemical studies. Proteins mutated in dystroglycanopathies are shown in red boxes, and their enzyme activities, where known, are indicated by arrows. POMT1 and POMT2 encode protein O-mannosyltransferases. Although this glycan was originally considered a candidate for the laminin-binding moiety (and mutation of POMT1, POMT2 or POMGnT1 results in dystroglycanopathy), enzymatic removal does not destroy the laminin-binding activity in vitro [9]. The recently described phosphomannose structure [8] contains an unknown structure (X) thought to be the glycan responsible for binding. LARGE and Fukutin (and probably FKRP) act downstream of the formation of this structure. Gal, galactose; GlcNAc, N-acetylglucosamine; Man, mannose; P, phosphorylation; Sia, sialic acid. (b) LARGE synthesizes a polysaccharide with repeating units of [Xyl(α1→3)GlcA(β1→3)] that is required for ligand-binding activity (star, xylose; diamond, GlcA). This structure is a good candidate for the X moiety attached to the phosphomannose in (a). The functions of Fukutin and FRKP and their relationship to the synthesis of this structure are currently unknown.

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