Bacterial β-Glucosidase Reveals the Structural and Functional Basis of Genetic Defects in Human Glucocerebrosidase 2 (GBA2)

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• 作者：Ratana Charoenwattanasatien ; Salila Pengthaisong ; Imogen Breen ; Risa Mutoh ; Sompong Sansenya ; Yanling Hua ; Anupong Tankrathok ; Liang Wu ; Chomphunuch Songsiriritthigul ; Hideaki Tanaka ; Spencer J. Williams ; Gideon J. Davies ; Genji Kurisu ; James R. Ketudat Cairns
• 刊名：ACS Chemical Biology
• 出版年：2016
• 出版时间：July 15, 2016
• 年：2016
• 卷：11
• 期：7
• 页码：1891-1900
• 全文大小：577K
• 年卷期：0
• ISSN：1554-8937

文摘

Human glucosylcerebrosidase 2 (GBA2) of the CAZy family GH116 is responsible for the breakdown of glycosphingolipids on the cytoplasmic face of the endoplasmic reticulum and Golgi apparatus. Genetic defects in GBA2 result in spastic paraplegia and cerebellar ataxia, while cross-talk between GBA2 and GBA1 glucosylceramidases may affect Gaucher disease. Here, we report the first three-dimensional structure for any GH116 enzyme, Thermoanaerobacterium xylanolyticum TxGH116 β-glucosidase, alone and in complex with diverse ligands. These structures allow identification of the glucoside binding and active site residues, which are shown to be conserved with GBA2. Mutagenic analysis of TxGH116 and structural modeling of GBA2 provide a detailed structural and functional rationale for pathogenic missense mutations of GBA2.