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Protein Stability, Folding and Misfolding in Human PGK1 Deficiency
Dipartimento di Biologia e Biotecnologie "L. Spallanzani", Università degli Studi di Pavia, Viale Taramelli, 3B, Pavia 27100, Italy
Department of Physical Chemistry, Faculty of Science, University of Granada, Av. Fuentenueva s/n, Granada 18071, Spain
* Author to whom correspondence should be addressed.
Received: 21 October 2013; in revised form: 6 December 2013 / Accepted: 13 December 2013 / Published: 18 December 2013
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
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Valentini, G.; Maggi, M.; Pey, A.L. Protein Stability, Folding and Misfolding in Human PGK1 Deficiency. Biomolecules 2013, 3, 1030-1052.
Valentini G, Maggi M, Pey AL. Protein Stability, Folding and Misfolding in Human PGK1 Deficiency. Biomolecules. 2013; 3(4):1030-1052.
Valentini, Giovanna; Maggi, Maristella; Pey, Angel L. 2013. "Protein Stability, Folding and Misfolding in Human PGK1 Deficiency." Biomolecules 3, no. 4: 1030-1052.