Cryo-EM structure provides insights into the dimer arrangement of the O-linked β-N-acetylglucosamine transferase OGT
Cryo-EM structure provides insights into the dimer arrangement of the O-linked β-N-acetylglucosamine transferase OGT
The O-linked β-N-acetylglucosamine modification is a core signalling mechanism, with erroneous patterns leading to cancer and neurodegeneration. Although thousands of proteins are subject to this modification, only a single essential glycosyltransferase catalyses its installation, the O-GlcNAc transferase, OGT. Previous studies have provided truncated structures of OGT through X-ray crystallography, but the full-length protein has never been observed. Here, we report a 5.3 Å cryo-EM model of OGT. We show OGT is a dimer, providing a structural basis for how some X-linked intellectual disability mutations at the interface may contribute to disease. We observe that the catalytic section of OGT abuts a 13.5 tetratricopeptide repeat unit region and find the relative positioning of these sections deviate from the previously proposed, X-ray crystallography-based model. We also note that OGT exhibits considerable heterogeneity in tetratricopeptide repeat units N-terminal to the dimer interface with repercussions for how OGT binds protein ligands and partners.
Meek, Richard W.
5fdcf8d0-6b07-4d63-b719-8302fdd7a056
Blaza, James N.
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Busmann, Jil A.
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Alteen, Matthew G.
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Vocadlo, David J.
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Davies, Gideon J.
61049906-cf8c-4c45-afb6-edbea5efd8f1
11 November 2021
Meek, Richard W.
5fdcf8d0-6b07-4d63-b719-8302fdd7a056
Blaza, James N.
ee1d7717-b86b-43e7-9c1e-5526b8c9ae24
Busmann, Jil A.
2195bbfc-54dd-4b7b-be9b-42c70b1236d1
Alteen, Matthew G.
af75d13d-fe74-4a55-a64e-99ea1d53d64f
Vocadlo, David J.
665c7d3d-08e8-459d-a93d-e466dbc97f4e
Davies, Gideon J.
61049906-cf8c-4c45-afb6-edbea5efd8f1
Meek, Richard W., Blaza, James N., Busmann, Jil A., Alteen, Matthew G., Vocadlo, David J. and Davies, Gideon J.
(2021)
Cryo-EM structure provides insights into the dimer arrangement of the O-linked β-N-acetylglucosamine transferase OGT.
Nature Communications, 12, [6508].
(doi:10.1038/s41467-021-26796-6).
Abstract
The O-linked β-N-acetylglucosamine modification is a core signalling mechanism, with erroneous patterns leading to cancer and neurodegeneration. Although thousands of proteins are subject to this modification, only a single essential glycosyltransferase catalyses its installation, the O-GlcNAc transferase, OGT. Previous studies have provided truncated structures of OGT through X-ray crystallography, but the full-length protein has never been observed. Here, we report a 5.3 Å cryo-EM model of OGT. We show OGT is a dimer, providing a structural basis for how some X-linked intellectual disability mutations at the interface may contribute to disease. We observe that the catalytic section of OGT abuts a 13.5 tetratricopeptide repeat unit region and find the relative positioning of these sections deviate from the previously proposed, X-ray crystallography-based model. We also note that OGT exhibits considerable heterogeneity in tetratricopeptide repeat units N-terminal to the dimer interface with repercussions for how OGT binds protein ligands and partners.
Text
s41467-021-26796-6
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Accepted/In Press date: 20 October 2021
Published date: 11 November 2021
Identifiers
Local EPrints ID: 476103
URI: http://eprints.soton.ac.uk/id/eprint/476103
ISSN: 2041-1723
PURE UUID: 08c00387-8a11-47a1-92d9-a86ebc4fc3bc
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Date deposited: 12 Apr 2023 14:09
Last modified: 17 Mar 2024 04:19
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Author:
Richard W. Meek
Author:
James N. Blaza
Author:
Jil A. Busmann
Author:
Matthew G. Alteen
Author:
David J. Vocadlo
Author:
Gideon J. Davies
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