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

[Image: see text] 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-tal...

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Autores principales: Charoenwattanasatien, Ratana, Pengthaisong, Salila, Breen, Imogen, Mutoh, Risa, Sansenya, Sompong, Hua, Yanling, Tankrathok, Anupong, Wu, Liang, Songsiriritthigul, Chomphunuch, Tanaka, Hideaki, Williams, Spencer J., Davies, Gideon J., Kurisu, Genji, Cairns, James R. Ketudat
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2016
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4949581/
https://www.ncbi.nlm.nih.gov/pubmed/27115290
http://dx.doi.org/10.1021/acschembio.6b00192
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author Charoenwattanasatien, Ratana
Pengthaisong, Salila
Breen, Imogen
Mutoh, Risa
Sansenya, Sompong
Hua, Yanling
Tankrathok, Anupong
Wu, Liang
Songsiriritthigul, Chomphunuch
Tanaka, Hideaki
Williams, Spencer J.
Davies, Gideon J.
Kurisu, Genji
Cairns, James R. Ketudat
author_facet Charoenwattanasatien, Ratana
Pengthaisong, Salila
Breen, Imogen
Mutoh, Risa
Sansenya, Sompong
Hua, Yanling
Tankrathok, Anupong
Wu, Liang
Songsiriritthigul, Chomphunuch
Tanaka, Hideaki
Williams, Spencer J.
Davies, Gideon J.
Kurisu, Genji
Cairns, James R. Ketudat
author_sort Charoenwattanasatien, Ratana
collection PubMed
description [Image: see text] 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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spelling pubmed-49495812016-07-21 Bacterial β-Glucosidase Reveals the Structural and Functional Basis of Genetic Defects in Human Glucocerebrosidase 2 (GBA2) Charoenwattanasatien, Ratana Pengthaisong, Salila Breen, Imogen Mutoh, Risa Sansenya, Sompong Hua, Yanling Tankrathok, Anupong Wu, Liang Songsiriritthigul, Chomphunuch Tanaka, Hideaki Williams, Spencer J. Davies, Gideon J. Kurisu, Genji Cairns, James R. Ketudat ACS Chem Biol [Image: see text] 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. American Chemical Society 2016-04-26 2016-07-15 /pmc/articles/PMC4949581/ /pubmed/27115290 http://dx.doi.org/10.1021/acschembio.6b00192 Text en Copyright © 2016 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
spellingShingle Charoenwattanasatien, Ratana
Pengthaisong, Salila
Breen, Imogen
Mutoh, Risa
Sansenya, Sompong
Hua, Yanling
Tankrathok, Anupong
Wu, Liang
Songsiriritthigul, Chomphunuch
Tanaka, Hideaki
Williams, Spencer J.
Davies, Gideon J.
Kurisu, Genji
Cairns, James R. Ketudat
Bacterial β-Glucosidase Reveals the Structural and Functional Basis of Genetic Defects in Human Glucocerebrosidase 2 (GBA2)
title Bacterial β-Glucosidase Reveals the Structural and Functional Basis of Genetic Defects in Human Glucocerebrosidase 2 (GBA2)
title_full Bacterial β-Glucosidase Reveals the Structural and Functional Basis of Genetic Defects in Human Glucocerebrosidase 2 (GBA2)
title_fullStr Bacterial β-Glucosidase Reveals the Structural and Functional Basis of Genetic Defects in Human Glucocerebrosidase 2 (GBA2)
title_full_unstemmed Bacterial β-Glucosidase Reveals the Structural and Functional Basis of Genetic Defects in Human Glucocerebrosidase 2 (GBA2)
title_short Bacterial β-Glucosidase Reveals the Structural and Functional Basis of Genetic Defects in Human Glucocerebrosidase 2 (GBA2)
title_sort bacterial β-glucosidase reveals the structural and functional basis of genetic defects in human glucocerebrosidase 2 (gba2)
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4949581/
https://www.ncbi.nlm.nih.gov/pubmed/27115290
http://dx.doi.org/10.1021/acschembio.6b00192
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