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Crystal structure of Thermotoga maritima alpha-L-fucosidase - Insights into the catalytic mechanism and the molecular basis for fucosidosis

TitleCrystal structure of Thermotoga maritima alpha-L-fucosidase - Insights into the catalytic mechanism and the molecular basis for fucosidosis
Publication TypeJournal Article
Year of Publication2004
AuthorsSulzenbacher, G, Bignon, C, Nishimura, T, Tarling, CA, Withers, SG, Henrissat, B, Bourne, Y
JournalJOURNAL OF BIOLOGICAL CHEMISTRY
Volume279
Pagination13119-13128
Date PublishedMAR 26
ISSN0021-9258
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 Bronsted 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.

DOI10.1074/jbc.M313783200