MPŠ MP&Scaron MP&Scaron MP&Scaron Avtorji

Jožef Stefan
Postgraduate School

Jamova 39
SI-1000 Ljubljana

Phone: +386 1 477 31 00
Fax: +386 1 477 31 10


Course Description

Stability, Folding and Aggregation of Proteins


Nanosciences and Nanotechnologies, third-level study programme


prof. dr. Eva Žerovnik


To enable students to understand the principles of protein folding and stability. Thermodynamic, kinetic and structural aspects are discussed. In addition, they become familiar with the associated mechanisms of protein aggregation which is involved in neurodegenerative diseases.


The subject comprises the following themes:
• Stability of proteins: basic knowledge of stability and its determination
• The problem of protein folding – folding in vitro and in vivo
• Kinetics, transition states and energy landscapes
• How does folding start? - detecting the early stages
• The molten globule – its relevance in folding, aggregation and protein translocation
• The enzymology of protein folding
• The role of chaperones in folding in vivo
• Aggregation to amyloid-fibrils: in vitro and in the cell
• Protein folding and disease; neurodegenerative diseases

Course literature:

Book: Mechanisms of Protein Folding, 2nd edn., (2000) R. H. Pain (ed.), Oxford University Press.

Additional book: Protein Folding-Misfolding: some current concepts of protein chemistry. Zbilut JP and Scheibel T (eds.), Nova Sci Publi., New York, 2007.

Additional book: Protein misfolding diseases; current and emerging therapies. eds Raminez-Alvarado, J.W. Kelly, C.M. Dobson, Wiley Series in Protein and Peptide Science, Series Ed. V.N. Uversky. John Wiley & Sons, New Jersey 2010.

Special issue of Current Opinion in Structural Biology vol 18, pp. 1- 130, 2008. Folding and Binding Itzhaki L and Wolynes P (eds.)

Selected papers:

Eichner T, Kalverda AP,. Thompson GS, Homans SW. and Radford SE (2011) Conformational Conversion during Amyloid Formation at Atomic Resolution. Molecular Cell 41: 161–172.

Sharma, S. et al. (2008). Monitoring protein conformation along the pathway of chaperone-assisted folding. Cell, 133,142-153.

Felitsky et al., (2008). Modeling transient collapsed states of an unfolded protein to provide insights into early folding events. Proc. Natl. Acad. Sci USA 105: 6278-6283.

Schuler and Eaton (2008). Protein folding studied by single-molecule FRET. Curr Opin. Struct. Biol.18: 16-26.

Ohnishi S and Takano K (2004): Amyloid fibrils from the viewpoint of protein folding. Cell Mol Life Sci. 61: 511-524.

Review papers:

Lashuel HA, Lansbury PT Jr. (2006) Are amyloid diseases caused by protein aggregates that mimic bacterial pore-forming toxins? Q Rev Biophys. 39, 167-201.

Significant publications and references:

Jelinska C, Davis PJ, Kenig M, et al. (2011) Modulation of Contact Order Effects in the Two-State Folding of Stefins A and B. Biophys.J. 100: 2268-2274.

Taler-Vercic A, Zerovnik E (2010) Binding of amyloid peptides to domain-swapped dimers of other amyloid-forming proteins may prevent their neurotoxicity. BIOESSAYS 32 : 1020-1024.

Škerget K, Taler-Verčič A, Bavdek A, et al. (2010) Interaction between Oligomers of Stefin B and Amyloid-beta in Vitro and in Cells J.Biol.Chem. 285: 3201-3210.

Morgan GJ, Giannini S, Hounslow AM, et al. (2008) Exclusion of the native alpha-helix from the amyloid fibrils of a mixed alpha/beta protein. J. Mol. Biol. 375: 487-498

Čeru, S and Žerovnik, E. (2008) Similar toxicity of the oligomeric molten globule state and the prefibrillar oligomers. FEBS lett. 582, 203-209.

Jenko Kokalj S, Guncar G, Stern I, et al. (2007) Essential role of proline isomerization in stefin B tetramer formation. J.Mol.Biol. 366: 1569-1579.

Lejeune A, Pain RH, Charlier P, Frčre JM, Matagne A. (2008): TEM-1 beta-lactamase folds in a non-hierarchical manner with transient non-native interactions involving the C-terminal region. Biochemistry47:1186 93

Kenig, M, Jenko-Kokalj, S, Tušek-Žnidarič, M, Pompe-Novak, M, Gunčar G, Turk D, Waltho JP, Staniforth, RA, Avbelj, F and Žerovnik, E (2006) Folding and amyloid-fibril formation for a series of human stefins' chimeras: Any correlation? Proteins 62, 918-927.

Staniforth RA, Dean JL, Zhong Q, Žerovnik E, Clarke AR, Waltho JP. (2000). The major transition state in folding need not involve the immobilization of side chains. Proc Natl Acad Sci U S A. 97, 5790-5795.

Jerala, R and Žerovnik, E. (1999) Accessing the global minimum conformation of stefin A dimer by annealing under partially denaturing conditions. J. mol. biol. 291, 1079-1089.

Žerovnik, E, Virden, R, Jerala, R, Kroon-Žitko L, Turk, V and Waltho, JP. (1999). Difference in the effects of TFE on the folding pathways of human stefins A and B. Proteins 36, 205-216.

Wheeler, K. A., Hawkins, A. R., Pain, R. H. and Virden, R. (1998): The slow step of folding of Staphylococcus aureus -lactamase involves the collapse of a surface loop rate limited by the trans to cis isomerization of a non-prolyl peptide bond. Proteins: Structure, Function and Genetics 33, 550-557.

Žerovnik, E., Jerala, R., Kroon-Žitko, L., Pain, R.H. and Turk, V. (1992). Intermediates in denaturation of a small globular protein, recombinant human stefin B. J. Biol. Chem. 267, 9041- 9046.

Ptitsyn, OB, Pain RH, Semisotnov GV, Žerovnik, E and Razgulyaev OI .Evidence for a molten globule state as a general intermediate in protein folding. FEBS lett. 262, 20-24 (1990).


• oral assessment

Students obligations:

• regular coursework, oral examination