Crystal structure of glycogen debranching enzyme and insights into its catalysis and disease-causing mutations

Liting Zhai; Lingling Feng; Lin Xia; Huiyong Yin; Song Xiang

doi:10.1038/ncomms11229

Crystal structure of glycogen debranching enzyme and insights into its catalysis and disease-causing mutations

Liting Zhai
, Lingling Feng
, Lin Xia
, Huiyong Yin
, Song Xiang^*

^*Corresponding author for this work

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

47 Citations (Scopus)

34 Downloads (CityUHK Scholars)

Abstract

Glycogen is a branched glucose polymer and serves as an important energy store. Its debranching is a critical step in its mobilization. In animals and fungi, the 170 kDa glycogen debranching enzyme (GDE) catalyses this reaction. GDE deficiencies in humans are associated with severe diseases collectively termed glycogen storage disease type III (GSDIII). We report crystal structures of GDE and its complex with oligosaccharides, and structure-guided mutagenesis and biochemical studies to assess the structural observations. These studies reveal that distinct domains in GDE catalyse sequential reactions in glycogen debranching, the mechanism of their catalysis and highly specific substrate recognition. The unique tertiary structure of GDE provides additional contacts to glycogen besides its active sites, and our biochemical experiments indicate that they mediate its recruitment to glycogen and regulate its activity. Combining the understanding of the GDE catalysis and functional characterizations of its disease-causing mutations provides molecular insights into GSDIII.

Original language	English
Article number	11229
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms11229
Publication status	Published - 18 Apr 2016
Externally published	Yes

Bibliographical note

Publication details (e.g. title, author(s), publication statuses and dates) are captured on an “AS IS” and “AS AVAILABLE” basis at the time of record harvesting from the data source. Suggestions for further amendments or supplementary information can be sent to [email protected].

Funding

This work is supported by the National Natural Science Foundation of China (general grant 31570743), Ministry of Science and Technology of China (973 program 2011CB910500) and the One Hundred Talents Program of the Chinese Academy of Sciences. We thank Professor Jianhua He and staff scientists at the Shanghai Synchrotron Radiation Facility beamline BL17U for assistance during diffraction data collection, the molecular biology core facility at Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences for assistance with dynamic light-scattering experiments, Zi Li at Institute for Nutritional Sciences, Chinese Academy of Sciences for assistance with GDE functional experiments, Ning Zhang at Shanghai Jiaotong University medical school for assistance in various aspects, Jonathan Valencia Swain at Institute for Nutritional Sciences, Chinese Academy of Sciences and Professor Liang Tong at Columbia University, USA for help in preparing the manuscript.

Publisher's Copyright Statement

This full text is made available under CC-BY 4.0. https://creativecommons.org/licenses/by/4.0/

Access Output

10.1038/ncomms11229

143102926.pdfFinal Published version, 2.18 MBLicence: CC BY

Other Access Options

Check CityUHK Library

Permanent Link

Right click to copy link

Cite this

@article{53c243957ccb402d8c33f995fdfb8f01,

title = "Crystal structure of glycogen debranching enzyme and insights into its catalysis and disease-causing mutations",

abstract = "Glycogen is a branched glucose polymer and serves as an important energy store. Its debranching is a critical step in its mobilization. In animals and fungi, the 170 kDa glycogen debranching enzyme (GDE) catalyses this reaction. GDE deficiencies in humans are associated with severe diseases collectively termed glycogen storage disease type III (GSDIII). We report crystal structures of GDE and its complex with oligosaccharides, and structure-guided mutagenesis and biochemical studies to assess the structural observations. These studies reveal that distinct domains in GDE catalyse sequential reactions in glycogen debranching, the mechanism of their catalysis and highly specific substrate recognition. The unique tertiary structure of GDE provides additional contacts to glycogen besides its active sites, and our biochemical experiments indicate that they mediate its recruitment to glycogen and regulate its activity. Combining the understanding of the GDE catalysis and functional characterizations of its disease-causing mutations provides molecular insights into GSDIII.",

author = "Liting Zhai and Lingling Feng and Lin Xia and Huiyong Yin and Song Xiang",

note = "Publication details (e.g. title, author(s), publication statuses and dates) are captured on an “AS IS” and “AS AVAILABLE” basis at the time of record harvesting from the data source. Suggestions for further amendments or supplementary information can be sent to [email protected].",

year = "2016",

month = apr,

day = "18",

doi = "10.1038/ncomms11229",

language = "English",

volume = "7",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Springer Nature",

}

TY - JOUR

T1 - Crystal structure of glycogen debranching enzyme and insights into its catalysis and disease-causing mutations

AU - Zhai, Liting

AU - Feng, Lingling

AU - Xia, Lin

AU - Yin, Huiyong

AU - Xiang, Song

N1 - Publication details (e.g. title, author(s), publication statuses and dates) are captured on an “AS IS” and “AS AVAILABLE” basis at the time of record harvesting from the data source. Suggestions for further amendments or supplementary information can be sent to [email protected].

PY - 2016/4/18

Y1 - 2016/4/18

N2 - Glycogen is a branched glucose polymer and serves as an important energy store. Its debranching is a critical step in its mobilization. In animals and fungi, the 170 kDa glycogen debranching enzyme (GDE) catalyses this reaction. GDE deficiencies in humans are associated with severe diseases collectively termed glycogen storage disease type III (GSDIII). We report crystal structures of GDE and its complex with oligosaccharides, and structure-guided mutagenesis and biochemical studies to assess the structural observations. These studies reveal that distinct domains in GDE catalyse sequential reactions in glycogen debranching, the mechanism of their catalysis and highly specific substrate recognition. The unique tertiary structure of GDE provides additional contacts to glycogen besides its active sites, and our biochemical experiments indicate that they mediate its recruitment to glycogen and regulate its activity. Combining the understanding of the GDE catalysis and functional characterizations of its disease-causing mutations provides molecular insights into GSDIII.

AB - Glycogen is a branched glucose polymer and serves as an important energy store. Its debranching is a critical step in its mobilization. In animals and fungi, the 170 kDa glycogen debranching enzyme (GDE) catalyses this reaction. GDE deficiencies in humans are associated with severe diseases collectively termed glycogen storage disease type III (GSDIII). We report crystal structures of GDE and its complex with oligosaccharides, and structure-guided mutagenesis and biochemical studies to assess the structural observations. These studies reveal that distinct domains in GDE catalyse sequential reactions in glycogen debranching, the mechanism of their catalysis and highly specific substrate recognition. The unique tertiary structure of GDE provides additional contacts to glycogen besides its active sites, and our biochemical experiments indicate that they mediate its recruitment to glycogen and regulate its activity. Combining the understanding of the GDE catalysis and functional characterizations of its disease-causing mutations provides molecular insights into GSDIII.

UR - https://www.scopus.com/pages/publications/84973369314

UR - https://www.scopus.com/record/pubmetrics.uri?eid=2-s2.0-84973369314&origin=recordpage

U2 - 10.1038/ncomms11229

DO - 10.1038/ncomms11229

M3 - RGC 21 - Publication in refereed journal

C2 - 27088557

SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

M1 - 11229

ER -

Crystal structure of glycogen debranching enzyme and insights into its catalysis and disease-causing mutations

Abstract

Bibliographical note

Funding

Publisher's Copyright Statement

Access Output

Other Access Options

Permanent Link

Other Files and Links

Fingerprint

Cite this