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Crystal Structure of Thermotoga maritima ␣-L-Fucosidase INSIGHTS INTO THE CATALYTIC MECHANISM AND THE MOLECULAR BASIS FOR FUCOSIDOSIS

Abstract : Fucosylated glycoconjugates are involved in numerous biological events, and ␣-L-fucosidases, the enzymes responsible for their processing, are therefore of crucial importance. Deficiency in ␣-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 ␣-L-fucosidase function at the molecular level, we have determined the crystal structure of Thermotoga maritima ␣-L-fucosidase. This enzyme assembles as a hexamer and displays a two-domain fold, composed of a catalytic (␤/␣) 8-like domain and a C-terminal ␤-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 ␣-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.
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https://hal.archives-ouvertes.fr/hal-03160668
Contributor : Gerlind Sulzenbacher Connect in order to contact the contributor
Submitted on : Friday, March 5, 2021 - 2:00:49 PM
Last modification on : Friday, January 21, 2022 - 10:52:01 AM
Long-term archiving on: : Sunday, June 6, 2021 - 6:55:25 PM

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Gerlind Sulzenbacher, Christophe Bignon, Takeshi Nishimura, Chris A Tarling, Stephen G Withers, et al.. Crystal Structure of Thermotoga maritima ␣-L-Fucosidase INSIGHTS INTO THE CATALYTIC MECHANISM AND THE MOLECULAR BASIS FOR FUCOSIDOSIS. Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2004, ⟨10.1074/jbc.M313783200⟩. ⟨hal-03160668⟩

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