protein folding

Protein folding in the endoplasmic reticulum (ER) must couple protein-synthesis pathways operating outside of the compartment with ER-assisted folding (ERAF) pathways in the lumen.

Proteins have to fold to a specific three-dimensional structure and function as a structural and/or chemical building block in living systems.

Energy landscape

The sequence of amino acids encodes this native structure as well as the “energy landscape” on which the protein searches out conformations.

The functional native state of the protein most often corresponds to the thermodynamic (free-energy) minimum conformation at physiological conditions.

In the ’energy landscape funnel model’, the free-energy of folding of a protein is represented in a diagram. The vertical dimension represents the free-energy with N, the native state, at a minimum energy. The width of the funnel represents the chain entropy and number of available configurations.

As the protein folds along one of the black lines, it travels from the lip of the funnel, where there are many conformations with equal energy to the one native state, no matter where it started from.

Pathology (Anomalies of protein folding or protein misfolding or protein misfolding diseases)

 protein aggregation diseases

The discovery of protein agregation diseases, however, where multiple proteins sacrifice contacts in the globular native state in favor of inter-chain contacts with neighboring proteins, suggests that some proteins have aggregated states that are thermodynamically equally if not more favorable than the native state.

Many of these agregates have a common morphology named amyloid fibrils, regular fibrillar structures micrometers in length, a few nanometers in diameter.

 chaperone proteins

Chaperone-mediated folding imbalances that are associated with numerous misfolding diseases, including diabetes, trigger the unfolded-protein response (UPR), using both transcriptional and translational pathways to correct the problem.

• diabetes
• amyloidosis
• fibrillin-1 mutations and Marfan disease (12651868)

 Folding@home (Stanford University, CA)

Videos

 Protein structure

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 Protein folding

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 Protein folding study on Playstation by Folding@home (Stanford University, CA)

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References

 From the first protein structures to our current knowledge of protein folding: delights and scepticisms. Fersht AR. Nat Rev Mol Cell Biol. 2008 Aug;9(8):650-4. PMID: 18578032

 Wiseman RL, Balch WE. A new pharmacology - drugging stressed folding pathways. Trends Mol Med. 2005 Aug;11(8):347-50. PMID: 16005683

 Ma Y, Hendershot LM. The role of the unfolded protein response in tumour development: friend or foe? Nat Rev Cancer. 2004 Dec;4(12):966-77. PMID: 15573118

 Daggett V, Fersht A. The present view of the mechanism of protein folding. Nat Rev Mol Cell Biol. 2003 Jun;4(6):497-502. PMID: 12778129

 Ursini F, Davies KJ, Maiorino M, Parasassi T, Sevanian A. Atherosclerosis: another protein misfolding disease? Trends Mol Med. 2002 Aug;8(8):370-4. PMID: 12127722

 Horwich A: Protein aggregation in disease: a role for folding intermediates forming specific multimeric interactions. J Clin Invest 110:1221, 2002.

 Hartl FU, Hayer-Hartl M: Molecular chaperones in the cytosol: from nascent chain to folded protein. Science 295:1852, 2002.

 Kuznetsov G, Nigam SK. Folding of secretory and membrane proteins. N Engl J Med 1998;339:1688-1695.