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.
Highlights
Protein folding inside eukaryotic cells is a complex process wherein folding of the newly synthesized polypeptide competes with aggregation and degradation [1]
We describe our recent efforts to understand the impact of mutations in folding and stability of the human phosphoglycerate kinase 1 enzyme, which are associated to hPGK1 deficiency, a conformational disease
Studies inside living cells and in the presence of macromolecular crowding agents have shown that physical and functional properties of PGK enzymes, including folding kinetics and stability, as well as the domain dynamics undergone along the catalytic cycle, may be strongly affected by macromolecular crowding in vivo [24,25,26]
Summary
Protein folding inside eukaryotic cells is a complex process wherein folding of the newly synthesized polypeptide competes with aggregation and degradation [1]. Studies inside living cells and in the presence of macromolecular crowding agents have shown that physical and functional properties of PGK enzymes, including folding kinetics and stability, as well as the domain dynamics undergone along the catalytic cycle, may be strongly affected by macromolecular crowding in vivo [24,25,26]. All these studies shed light on the changes in protein denaturation energetics and folding/unfolding cooperativity in an evolutionary perspective
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