Protein Stability, Folding and Misfolding in Human PGK1 Deficiency

Biomolecules

Giovanna Valentini¹  Maristella Maggi¹ 

[1] Dipartimento di Biologia e Biotecnologie “L. Spallanzani”, Università degli Studi di Pavia, Viale Taramelli, 3B, Pavia 27100, Italy; E-Mail:

关键词: protein misfolding;    protein aggregation;    conformational disease;    pharmacological therapies;    molecular chaperones;    thermodynamic stability;    kinetic stability;    proteolysis;   

DOI  :  10.3390/biom3041030

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2013 by the authors; licensee MDPI, Basel, Switzerland.