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....
Main Authors: | , , |
---|---|
Format: | Article |
Language: | English |
Published: |
MDPI AG
2013-12-01
|
Series: | Biomolecules |
Subjects: | |
Online Access: | http://www.mdpi.com/2218-273X/3/4/1030 |
id |
doaj-e49cbd16ddd74001b4f4ac98ad352ce6 |
---|---|
record_format |
Article |
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 |
work_keys_str_mv |
AT giovannavalentini proteinstabilityfoldingandmisfoldinginhumanpgk1deficiency AT maristellamaggi proteinstabilityfoldingandmisfoldinginhumanpgk1deficiency AT angellpey proteinstabilityfoldingandmisfoldinginhumanpgk1deficiency |
_version_ |
1725619956488339456 |