Heterodimerization of Two Pathological Mutants Enhances the Activity of Human Phosphomannomutase2

The most frequent disorder of glycosylation is due to mutations in the gene encoding phosphomannomutase2 (PMM2-CDG). For this disease, which is autosomal and recessive, there is no cure at present. Most patients are composite heterozygous and carry one allele encoding an inactive mutant, R141H, and...

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Main Authors:	Andreotti, Giuseppina, Monti, Maria Chiara, Citro, Valentina, Cubellis, Maria Vittoria
Format:	Online
Language:	English
Published:	Public Library of Science 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4619449/

id	pubmed-4619449
recordtype	oai_dc
spelling	pubmed-46194492015-10-29 Heterodimerization of Two Pathological Mutants Enhances the Activity of Human Phosphomannomutase2 Andreotti, Giuseppina Monti, Maria Chiara Citro, Valentina Cubellis, Maria Vittoria Research Article The most frequent disorder of glycosylation is due to mutations in the gene encoding phosphomannomutase2 (PMM2-CDG). For this disease, which is autosomal and recessive, there is no cure at present. Most patients are composite heterozygous and carry one allele encoding an inactive mutant, R141H, and one encoding a hypomorphic mutant. Phosphomannomutase2 is a dimer. We reproduced composite heterozygosity in vitro by mixing R141H either with the wild type protein or the most common hypomorphic mutant F119L and compared the quaternary structure, the activity and the stability of the heterodimeric enzymes. We demonstrated that the activity of R141H/F119L heterodimers in vitro, which reproduces the protein found in patients, has the same activity of wild type/R141H, which reproduces the protein found in healthy carriers. On the other hand the stability of R141H/F119L appears to be reduced both in vitro and in vivo. These findings suggest that a therapy designed to enhance protein stability such as those based on pharmacological chaperones or modulation of proteostasis could be beneficial for PMM2-CDG patients carrying R141H/F119L genotype as well as for other genotypes where protein stability rather than specific activity is affected by mutations. Public Library of Science 2015-10-21 /pmc/articles/PMC4619449/ /pubmed/26488408 http://dx.doi.org/10.1371/journal.pone.0139882 Text en © 2015 Andreotti et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Andreotti, Giuseppina Monti, Maria Chiara Citro, Valentina Cubellis, Maria Vittoria
spellingShingle	Andreotti, Giuseppina Monti, Maria Chiara Citro, Valentina Cubellis, Maria Vittoria Heterodimerization of Two Pathological Mutants Enhances the Activity of Human Phosphomannomutase2
author_facet	Andreotti, Giuseppina Monti, Maria Chiara Citro, Valentina Cubellis, Maria Vittoria
author_sort	Andreotti, Giuseppina
title	Heterodimerization of Two Pathological Mutants Enhances the Activity of Human Phosphomannomutase2
title_short	Heterodimerization of Two Pathological Mutants Enhances the Activity of Human Phosphomannomutase2
title_full	Heterodimerization of Two Pathological Mutants Enhances the Activity of Human Phosphomannomutase2
title_fullStr	Heterodimerization of Two Pathological Mutants Enhances the Activity of Human Phosphomannomutase2
title_full_unstemmed	Heterodimerization of Two Pathological Mutants Enhances the Activity of Human Phosphomannomutase2
title_sort	heterodimerization of two pathological mutants enhances the activity of human phosphomannomutase2
description	The most frequent disorder of glycosylation is due to mutations in the gene encoding phosphomannomutase2 (PMM2-CDG). For this disease, which is autosomal and recessive, there is no cure at present. Most patients are composite heterozygous and carry one allele encoding an inactive mutant, R141H, and one encoding a hypomorphic mutant. Phosphomannomutase2 is a dimer. We reproduced composite heterozygosity in vitro by mixing R141H either with the wild type protein or the most common hypomorphic mutant F119L and compared the quaternary structure, the activity and the stability of the heterodimeric enzymes. We demonstrated that the activity of R141H/F119L heterodimers in vitro, which reproduces the protein found in patients, has the same activity of wild type/R141H, which reproduces the protein found in healthy carriers. On the other hand the stability of R141H/F119L appears to be reduced both in vitro and in vivo. These findings suggest that a therapy designed to enhance protein stability such as those based on pharmacological chaperones or modulation of proteostasis could be beneficial for PMM2-CDG patients carrying R141H/F119L genotype as well as for other genotypes where protein stability rather than specific activity is affected by mutations.
publisher	Public Library of Science
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4619449/
_version_	1613492579576315904

Heterodimerization of Two Pathological Mutants Enhances the Activity of Human Phosphomannomutase2

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