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The primary familial brain calcification-associated protein MYORG is an α-galactosidase with restricted substrate specificity

Primary familial brain calcification (PFBC) is characterised by abnormal deposits of calcium phosphate within various regions of the brain that are associated with severe cognitive impairments, psychiatric conditions, and movement disorders. Recent studies in diverse populations have shown a link be...

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Autores principales: Meek, Richard W., Brockerman, Jacob, Fordwour, Osei B., Zandberg, Wesley F., Davies, Gideon J., Vocadlo, David J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9491548/
https://www.ncbi.nlm.nih.gov/pubmed/36129849
http://dx.doi.org/10.1371/journal.pbio.3001764
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author Meek, Richard W.
Brockerman, Jacob
Fordwour, Osei B.
Zandberg, Wesley F.
Davies, Gideon J.
Vocadlo, David J.
author_facet Meek, Richard W.
Brockerman, Jacob
Fordwour, Osei B.
Zandberg, Wesley F.
Davies, Gideon J.
Vocadlo, David J.
author_sort Meek, Richard W.
collection PubMed
description Primary familial brain calcification (PFBC) is characterised by abnormal deposits of calcium phosphate within various regions of the brain that are associated with severe cognitive impairments, psychiatric conditions, and movement disorders. Recent studies in diverse populations have shown a link between mutations in myogenesis-regulating glycosidase (MYORG) and the development of this disease. MYORG is a member of glycoside hydrolase (GH) family 31 (GH31) and, like the other mammalian GH31 enzyme α-glucosidase II, this enzyme is found in the lumen of the endoplasmic reticulum (ER). Though presumed to act as an α-glucosidase due to its localization and sequence relatedness to α-glucosidase II, MYORG has never been shown to exhibit catalytic activity. Here, we show that MYORG is an α-galactosidase and present the high-resolution crystal structure of MYORG in complex with substrate and inhibitor. Using these structures, we map detrimental mutations that are associated with MYORG-associated brain calcification and define how these mutations may drive disease progression through loss of enzymatic activity. Finally, we also detail the thermal stabilisation of MYORG afforded by a clinically approved small molecule ligand, opening the possibility of using pharmacological chaperones to enhance the activity of mutant forms of MYORG.
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spelling pubmed-94915482022-09-22 The primary familial brain calcification-associated protein MYORG is an α-galactosidase with restricted substrate specificity Meek, Richard W. Brockerman, Jacob Fordwour, Osei B. Zandberg, Wesley F. Davies, Gideon J. Vocadlo, David J. PLoS Biol Research Article Primary familial brain calcification (PFBC) is characterised by abnormal deposits of calcium phosphate within various regions of the brain that are associated with severe cognitive impairments, psychiatric conditions, and movement disorders. Recent studies in diverse populations have shown a link between mutations in myogenesis-regulating glycosidase (MYORG) and the development of this disease. MYORG is a member of glycoside hydrolase (GH) family 31 (GH31) and, like the other mammalian GH31 enzyme α-glucosidase II, this enzyme is found in the lumen of the endoplasmic reticulum (ER). Though presumed to act as an α-glucosidase due to its localization and sequence relatedness to α-glucosidase II, MYORG has never been shown to exhibit catalytic activity. Here, we show that MYORG is an α-galactosidase and present the high-resolution crystal structure of MYORG in complex with substrate and inhibitor. Using these structures, we map detrimental mutations that are associated with MYORG-associated brain calcification and define how these mutations may drive disease progression through loss of enzymatic activity. Finally, we also detail the thermal stabilisation of MYORG afforded by a clinically approved small molecule ligand, opening the possibility of using pharmacological chaperones to enhance the activity of mutant forms of MYORG. Public Library of Science 2022-09-21 /pmc/articles/PMC9491548/ /pubmed/36129849 http://dx.doi.org/10.1371/journal.pbio.3001764 Text en © 2022 Meek et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Meek, Richard W.
Brockerman, Jacob
Fordwour, Osei B.
Zandberg, Wesley F.
Davies, Gideon J.
Vocadlo, David J.
The primary familial brain calcification-associated protein MYORG is an α-galactosidase with restricted substrate specificity
title The primary familial brain calcification-associated protein MYORG is an α-galactosidase with restricted substrate specificity
title_full The primary familial brain calcification-associated protein MYORG is an α-galactosidase with restricted substrate specificity
title_fullStr The primary familial brain calcification-associated protein MYORG is an α-galactosidase with restricted substrate specificity
title_full_unstemmed The primary familial brain calcification-associated protein MYORG is an α-galactosidase with restricted substrate specificity
title_short The primary familial brain calcification-associated protein MYORG is an α-galactosidase with restricted substrate specificity
title_sort primary familial brain calcification-associated protein myorg is an α-galactosidase with restricted substrate specificity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9491548/
https://www.ncbi.nlm.nih.gov/pubmed/36129849
http://dx.doi.org/10.1371/journal.pbio.3001764
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