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Biomolecules 2013, 3(4), 1030-1052; doi:10.3390/biom3041030
Review

Protein Stability, Folding and Misfolding in Human PGK1 Deficiency

1
, 1
 and 2,*
Received: 21 October 2013; in revised form: 6 December 2013 / Accepted: 13 December 2013 / Published: 18 December 2013
(This article belongs to the Special Issue Protein Folding and Misfolding)
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Abstract: 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.
Keywords: protein misfolding; protein aggregation; conformational disease; pharmacological therapies; molecular chaperones; thermodynamic stability; kinetic stability; proteolysis protein misfolding; protein aggregation; conformational disease; pharmacological therapies; molecular chaperones; thermodynamic stability; kinetic stability; proteolysis
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

Valentini, G.; Maggi, M.; Pey, A.L. Protein Stability, Folding and Misfolding in Human PGK1 Deficiency. Biomolecules 2013, 3, 1030-1052.

AMA Style

Valentini G, Maggi M, Pey AL. Protein Stability, Folding and Misfolding in Human PGK1 Deficiency. Biomolecules. 2013; 3(4):1030-1052.

Chicago/Turabian Style

Valentini, Giovanna; Maggi, Maristella; Pey, Angel L. 2013. "Protein Stability, Folding and Misfolding in Human PGK1 Deficiency." Biomolecules 3, no. 4: 1030-1052.



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