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

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

doi:10.1021/acschembio.6b00192

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

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

^*Corresponding author for this work

Chemistry

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	1891-1900
Number of pages	10
Journal	ACS Chemical Biology
Volume	11
Issue number	7
Early online date	26 Apr 2016
DOIs	https://doi.org/10.1021/acschembio.6b00192
Publication status	Published - 15 Jul 2016

Bibliographical note

© American Chemical Society 2016. This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

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10.1021/acschembio.6b00192

acschembio2E6b00192
© American Chemical Society 2016. This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
Final published version, 5.09 MBLicence: Other

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Charoenwattanasatien, R., Pengthaisong, S., Breen, I., Mutoh, R., Sansenya, S., Hua, Y., Tankrathok, A., Wu, L., Songsiriritthigul, C., Tanaka, H., Williams, S. J., Davies, G. J., Kurisu, G., & Cairns, J. R. K. (2016). Bacterial β-Glucosidase Reveals the Structural and Functional Basis of Genetic Defects in Human Glucocerebrosidase 2 (GBA2). ACS Chemical Biology, 11(7), 1891-1900. https://doi.org/10.1021/acschembio.6b00192

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

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.",

author = "Ratana Charoenwattanasatien and Salila Pengthaisong and Imogen Breen and Risa Mutoh and Sompong Sansenya and Yanling Hua and Anupong Tankrathok and Liang Wu and Chomphunuch Songsiriritthigul and Hideaki Tanaka and Williams, {Spencer J.} and Davies, {Gideon J.} and Genji Kurisu and Cairns, {James R Ketudat}",

note = "{\textcopyright} American Chemical Society 2016. This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.",

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Charoenwattanasatien, R, Pengthaisong, S, Breen, I, Mutoh, R, Sansenya, S, Hua, Y, Tankrathok, A, Wu, L, Songsiriritthigul, C, Tanaka, H, Williams, SJ, Davies, GJ, Kurisu, G & Cairns, JRK 2016, 'Bacterial β-Glucosidase Reveals the Structural and Functional Basis of Genetic Defects in Human Glucocerebrosidase 2 (GBA2)', ACS Chemical Biology, vol. 11, no. 7, pp. 1891-1900. https://doi.org/10.1021/acschembio.6b00192

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AU - Charoenwattanasatien, Ratana

AU - Pengthaisong, Salila

AU - Breen, Imogen

AU - Mutoh, Risa

AU - Sansenya, Sompong

AU - Hua, Yanling

AU - Tankrathok, Anupong

AU - Wu, Liang

AU - Songsiriritthigul, Chomphunuch

AU - Tanaka, Hideaki

AU - Williams, Spencer J.

AU - Davies, Gideon J.

AU - Kurisu, Genji

AU - Cairns, James R Ketudat

N1 - © American Chemical Society 2016. This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

PY - 2016/7/15

Y1 - 2016/7/15

N2 - 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.

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

Abstract

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