Protein Stability, Folding and Misfolding in Human PGK1 Deficiency

Conformational diseases are often caused by mutations, altering protein folding and stability in vivo. We review here our recent work on the effects of mutations on the human phosphoglycerate kinase 1 (hPGK1), with a particular focus on thermodynamics and kinetics of protein folding and misfolding....

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Main Authors: Giovanna Valentini, Maristella Maggi, Angel L. Pey
Format: Article
Language:English
Published: MDPI AG 2013-12-01
Series:Biomolecules
Subjects:
Online Access:http://www.mdpi.com/2218-273X/3/4/1030
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spelling doaj-e49cbd16ddd74001b4f4ac98ad352ce62020-11-24T23:07:07ZengMDPI AGBiomolecules2218-273X2013-12-01341030105210.3390/biom3041030biom3041030Protein Stability, Folding and Misfolding in Human PGK1 DeficiencyGiovanna Valentini0Maristella Maggi1Angel L. Pey2Dipartimento di Biologia e Biotecnologie "L. Spallanzani", Università degli Studi di Pavia, Viale Taramelli, 3B, Pavia 27100, ItalyDipartimento di Biologia e Biotecnologie "L. Spallanzani", Università degli Studi di Pavia, Viale Taramelli, 3B, Pavia 27100, ItalyDepartment of Physical Chemistry, Faculty of Science, University of Granada, Av. Fuentenueva s/n, Granada 18071, SpainConformational diseases are often caused by mutations, altering protein folding and stability in vivo. We review here our recent work on the effects of mutations on the human phosphoglycerate kinase 1 (hPGK1), with a particular focus on thermodynamics and kinetics of protein folding and misfolding. Expression analyses and in vitro biophysical studies indicate that disease-causing mutations enhance protein aggregation propensity. We found a strong correlation among protein aggregation propensity, thermodynamic stability, cooperativity and dynamics. Comparison of folding and unfolding properties with previous reports in PGKs from other species suggests that hPGK1 is very sensitive to mutations leading to enhance protein aggregation through changes in protein folding cooperativity and the structure of the relevant denaturation transition state for aggregation. Overall, we provide a mechanistic framework for protein misfolding of hPGK1, which is insightful to develop new therapeutic strategies aimed to target native state stability and foldability in hPGK1 deficient patients.http://www.mdpi.com/2218-273X/3/4/1030protein misfoldingprotein aggregationconformational diseasepharmacological therapiesmolecular chaperonesthermodynamic stabilitykinetic stabilityproteolysis
collection DOAJ
language English
format Article
sources DOAJ
author Giovanna Valentini
Maristella Maggi
Angel L. Pey
spellingShingle Giovanna Valentini
Maristella Maggi
Angel L. Pey
Protein Stability, Folding and Misfolding in Human PGK1 Deficiency
Biomolecules
protein misfolding
protein aggregation
conformational disease
pharmacological therapies
molecular chaperones
thermodynamic stability
kinetic stability
proteolysis
author_facet Giovanna Valentini
Maristella Maggi
Angel L. Pey
author_sort Giovanna Valentini
title Protein Stability, Folding and Misfolding in Human PGK1 Deficiency
title_short Protein Stability, Folding and Misfolding in Human PGK1 Deficiency
title_full Protein Stability, Folding and Misfolding in Human PGK1 Deficiency
title_fullStr Protein Stability, Folding and Misfolding in Human PGK1 Deficiency
title_full_unstemmed Protein Stability, Folding and Misfolding in Human PGK1 Deficiency
title_sort protein stability, folding and misfolding in human pgk1 deficiency
publisher MDPI AG
series Biomolecules
issn 2218-273X
publishDate 2013-12-01
description Conformational diseases are often caused by mutations, altering protein folding and stability in vivo. We review here our recent work on the effects of mutations on the human phosphoglycerate kinase 1 (hPGK1), with a particular focus on thermodynamics and kinetics of protein folding and misfolding. Expression analyses and in vitro biophysical studies indicate that disease-causing mutations enhance protein aggregation propensity. We found a strong correlation among protein aggregation propensity, thermodynamic stability, cooperativity and dynamics. Comparison of folding and unfolding properties with previous reports in PGKs from other species suggests that hPGK1 is very sensitive to mutations leading to enhance protein aggregation through changes in protein folding cooperativity and the structure of the relevant denaturation transition state for aggregation. Overall, we provide a mechanistic framework for protein misfolding of hPGK1, which is insightful to develop new therapeutic strategies aimed to target native state stability and foldability in hPGK1 deficient patients.
topic protein misfolding
protein aggregation
conformational disease
pharmacological therapies
molecular chaperones
thermodynamic stability
kinetic stability
proteolysis
url http://www.mdpi.com/2218-273X/3/4/1030
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AT maristellamaggi proteinstabilityfoldingandmisfoldinginhumanpgk1deficiency
AT angellpey proteinstabilityfoldingandmisfoldinginhumanpgk1deficiency
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