PMID:14715651
| Citation |
Sulzenbacher, G, Bignon, C, Nishimura, T, Tarling, CA, Withers, SG, Henrissat, B and Bourne, Y (2004) Crystal structure of Thermotoga maritima alpha-L-fucosidase. Insights into the catalytic mechanism and the molecular basis for fucosidosis. J. Biol. Chem. 279:13119-28 |
|---|---|
| Abstract |
Fucosylated glycoconjugates are involved in numerous biological events, and alpha-l-fucosidases, the enzymes responsible for their processing, are therefore of crucial importance. Deficiency in alpha-l-fucosidase activity is associated with fucosidosis, a lysosomal storage disorder characterized by rapid neurodegeneration, resulting in severe mental and motor deterioration. To gain insight into alpha-l-fucosidase function at the molecular level, we have determined the crystal structure of Thermotoga maritima alpha-l-fucosidase. This enzyme assembles as a hexamer and displays a two-domain fold, composed of a catalytic (beta/alpha)(8)-like domain and a C-terminal beta-sandwich domain. The structures of an enzyme-product complex and of a covalent glycosyl-enzyme intermediate, coupled with kinetic and mutagenesis studies, allowed us to identify the catalytic nucleophile, Asp(244), and the Brønsted acid/base, Glu(266). Because T. maritima alpha-l-fucosidase occupies a unique evolutionary position, being far more closely related to the mammalian enzymes than to any other prokaryotic homolog, a structural model of the human enzyme was built to document the structural consequences of the genetic mutations associated with fucosidosis. |
| Links |
PubMed Online version:10.1074/jbc.M313783200 |
| Keywords |
Catalysis; Catalytic Domain; Cloning, Molecular; Crystallography, X-Ray; Evolution, Molecular; Fucosidosis/metabolism; Humans; Kinetics; Models, Molecular; Mutagenesis, Site-Directed; Mutation; Phylogeny; Protein Conformation; Protein Folding; Protein Structure, Tertiary; Thermotoga maritima/enzymology; alpha-L-Fucosidase/chemistry |
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