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

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

  • ACS Chem Biol. 2016 Jul 15;11(7):1891-900. doi: 10.1021/acschembio.6b00192.
Ratana Charoenwattanasatien 1 2 3,  Salila Pengthaisong 2 3,  Imogen Breen 4,  Risa Mutoh 1,  Sompong Sansenya 5,  Yanling Hua 3 6,  Anupong Tankrathok 7,  Liang Wu 4,  Chomphunuch Songsiriritthigul 3 8,  Hideaki Tanaka 1,  Spencer J Williams 9,  Gideon J Davies 4,  Genji Kurisu 1,  James R Ketudat Cairns 2 3 10
Affiliations

Affiliations

  • 1 Institute for Protein Research, Osaka University , 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
  • 2 School of Biochemistry, Institute of Science, Suranaree Univerity of Technology , Nakhon Ratchasima 30000, Thailand.
  • 3 Center for Biomolecular Structure, Function and Application, Suranaree University of Technology , Nakhon Ratchasima 30000, Thailand.
  • 4 Structural Biology Laboratory, Department of Chemistry, The University of York , York YO10 5DD, United Kingdom.
  • 5 Department of Chemistry, Faculty of Science, Rajamangala University of Technology , Thanyaburi, Pathum Thani 12110, Thailand.
  • 6 Center for Scientific and Technological Equipment, Suranaree University of Technology , Nakhon Ratchasima 30000, Thailand.
  • 7 Department of Biotechnology, Faculty of Agro-Industrial Technology, Kalasin University , Kalasin 46000, Thailand.
  • 8 Synchrotron Light Research Institute , Nakhon Ratchasima 30000, Thailand.
  • 9 School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne , Parkville, Victoria 3010, Australia.
  • 10 Laboratory of Biochemistry, Chulabhorn Research Institute , Bangkok 10210, Thailand.
PMID: 27115290 DOI: 10.1021/acschembio.6b00192
Abstract

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.

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