Download MendeleyCrystal Structure of Thermotoga Maritima {Alpha}-L-Fucosidase: Insights Into the Catalytic Mechanism and the Molecular Basis for Fucosidosis
Sulzenbacher, G., Bignon, C., Nishimura, T., Tarling, C., Withers, S., Henrissat, B., Bourne, Y.(2004) J Biol Chem 279: 13119
- PubMed: 14715651
- DOI: https://doi.org/10.1074/jbc.M313783200
- Primary Citation of Related Structures:
1HL8, 1HL9, 1ODU - PubMed 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 Br?nsted 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.
Organizational Affiliation:
Architecture et Fonction des Macromol¨¦cules Biologiques, UMR 6098, CNRS, and Universit¨¦s Aix-Marseille I and II, 31 Chemin J. Aiguier, F-13402 Marseille Cedex 20, France.
