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

TY - JOUR

T1 - Bacterial β-Glucosidase Reveals the Structural and Functional Basis of Genetic Defects in Human Glucocerebrosidase 2 (GBA2)

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.

UR - http://www.scopus.com/inward/record.url?scp=84978760267&partnerID=8YFLogxK

U2 - 10.1021/acschembio.6b00192

DO - 10.1021/acschembio.6b00192

M3 - Article

AN - SCOPUS:84978760267

SN - 1554-8929

VL - 11

SP - 1891

EP - 1900

JO - ACS Chemical Biology

JF - ACS Chemical Biology

IS - 7

ER -