Bacterial β-Glucosidase Reveals the Structural and Functional Basis of Genetic Defects in Human Glucocerebrosidase 2 (GBA2)
| Autor: | Hideaki Tanaka, Spencer J. Williams, Imogen Breen, S. Pengthaisong, Genji Kurisu, Sompong Sansenya, Liang Wu, Chomphunuch Songsiriritthigul, Gideon J. Davies, Risa Mutoh, James R. Ketudat Cairns, Yanling Hua, Anupong Tankrathok, Ratana Charoenwattanasatien |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
CAZy Mutation Missense Biology Crystallography X-Ray medicine.disease_cause Biochemistry 03 medical and health sciences symbols.namesake 0302 clinical medicine Catalytic Domain medicine Humans Missense mutation Genetics Mutation Cerebellar ataxia beta-Glucosidase Endoplasmic reticulum Active site Articles General Medicine Golgi apparatus 030104 developmental biology symbols biology.protein Glucosylceramidase Molecular Medicine medicine.symptom Thermoanaerobacterium Glucocerebrosidase 030217 neurology & neurosurgery |
| Zdroj: | ACS Chemical Biology |
| ISSN: | 1554-8937 1554-8929 |
| DOI: | 10.1021/acschembio.6b00192 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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