Folding and Stability

On first sight the folding process of /1-proteins appears to be much more complex than that of a-proteins. This does not apply, however, for 

In vivo, the folding process may be supported by a periplasmic chaperone called Skp. Skp is a 17 kDa protein associated with the plasma membrane that, together with peptidyl prolyl isomerases and disulfideexchanging enzymes, helps folding freshly synthesized proteins in the periplasm (Schafer et al., 1999). Skp binds to partially unfolded polypeptides. Depending on the presence of phospholipids, lipopolysaccharides, and bivalent cations, Skp exists in two conformations, one of which is protease-sensitive (DeCock et al., 1999). Moreover, it was shown that Skp binds to unfolded periplasmic proteins and inserts into phospholipid monolayers, corroborating its putative role as helper in folding and membrane insertion. 

The stability of the /3-barrel itself was demonstrated in engineering experiments with OmpA. The four external loops of OmpA were replaced by shortcuts in all possible combinations (Koebnik, 1999). The resulting deletion mutants lost their biological functions in bacterial / -conjugation and as bacteriophage receptors, but kept the transmembrane /1-barrel as demonstrated by their resistance to proteolysis and thermal denaturation. The results confirm the expectation that the large external loops do not contribute to /1-barrel folding and stability. 

Fragments of natural coiled coils, even when they are of considerable size, rarely fold [see, for example, Trybus et al (1997) for an analysis of the myosin rod]. This may well serve a biological purpose, since a coiled coil the size of myosin might find it difficult to reach its proper register if local coiled-coil interactions formed rapidly and randomly along the 

Mosavi et al., 2002), that the consensus sequence embodies the most stable form of that particular fold. In that respect, it is noteworthy that coiled coils in archaea (e.g., prefoldin), which have a greater stability than their homologs in eukaryotes, match consensus matrices of coiled-coil sequences better, even though they did not contribute to them (A. Lupas, unpublished observation). 

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Dill, KA. Theory for the folding and stability of globular proteins. Biochemistry 24 1501-1509, 1985. 

As stated above, the most important missing piece in protein folding theory is an accurate all-atom potential. Recently there has been much effort in this direction, and much more is needed [48,55,72-77]. The existence of a potential satisfying minimal criteria such as folding and stability for a single protein was demonstrated in [73]. It is not a realistic potential by any means, but its existence validates the all-atom, implicit solvent, Monte Carlo approach as a serious candidate for theory. The method used to derive this potential was ad hoc, and has recently been compared with other standard methods in a rigorous and illuminating study [77]. 

Dantas G, Kuhlman B, Callender D, Wong M, Baker D. A large scale test of computational protein design folding and stability of nine completely redesigned globular proteins. J Mol Biol 2003 332 449-60. 

Colombo, G., Roccatano, D., and Mark, A. E. (2002). Folding and stability of the three-stranded beta-sheet peptide betanova Insights from molecular dynamics simulations. Proteins Strud. Fund. Genet. 46, 380—392. 

Santiveri, C. M., Jimenez, M. A., Rico, M., van Gunsteren, W. F., and Daura, X. (2002). /3-Hairpin folding and stability Molecular dynamics simulations of designed peptides in aqueous solution. Submitted. 

In biochemical systems, acid-base and redox reactions are essential. Electron transfer plays an obvious, crucial role in photosynthesis, and redox reactions are central to the response to oxidative stress, and to the innate immune system and inflammatory response. Acid-base and proton transfer reactions are a part of most enzyme mechanisms, and are also closely linked to protein folding and stability. Proton and electron transfer are often coupled, as in almost all the steps of the mitochondrial respiratory chain. 

Uhlmann, H., Iametti, S., Vecchio, G., Bonomi, R, and Bernhardt, R. 1997. Prol08 is important for folding and stabilization of adrenal ferredoxin, but does not influence the functional properties of the protein. European Journal of Biochemistry 248 897-902. 

Kihara, A., and Ito, K. (1998). Translocation, folding, and stability of the hflkc complex with signal anchor topogenic sequences./. Biol. Chem. 273, 29770-29775. 

Fig. 11. Effects of histone acetylation on the folding and stability of the nucleosome core particle. A. NaCl dependence of the sedimentation coefficient (s2o,w) of the nucleosome core particles with different extent of acetylation soo D] [379]. B. Dose-response curves obtained with hypo- ( ) and hyperacetylated...

E.S. Eberhardt, R.T. Raines, Amide-amide and amide-water hydrogen bonds Implications for protein folding and stability, J. Am. Chem. Soc. 116 (1994) 2149-2150. 

Prieto, J., M. WUmans, M.A. Jimenez, M. Rico, and L. Serrano, Non-native local interactions in protein folding and stability intro-... 

Knhlman, B., J.A. Boice, W.J. Wn, R. Fairman, and D.P. Raleigh, Calcium binding peptides from alpha-lactalbumin implications for protein folding and stability. Biochemistry, 1997.36(15) 4607-15. 

Ritco-Vonsovici, M. Mouratou, B. Minard, P Desmadril, M. Yon, J.M. Andrieux, M. Leroy, E. Guittet, E. Role of the C-terminal helix in the folding and stability of yeast phosphoglycerate kinase. Biochemistry, 34, 833-841 (1995)... 

Many cell surface or extracellular proteins are glycoproteins, as are most secreted proteins. The covalently attached oligosaccharides influence the folding and stability of the proteins, provide critical information about the... 

The active site is in a cleft between a large domain with a nonpolar core and a smaller (3-sheet domain that contains many hydrogen-bonded polar side chains (Figs. 12-3,12-4). Human lysozyme has a similar structure and properties.57-59 The T4 lysozyme has an additional C-terminal domain whose function may be to bind the crosslinking peptide of the E. coli peptidoglycan. Goose lysozyme is similar in part to both hen lysozyme and T4 lysozyme. All three enzymes, as well as that of our own tears, may have evolved from a common ancestral protein.60 On the other hand, Streptomyces erythaeus has developed its own lysozyme with a completely different structure.61 An extensive series of T4 lysozyme mutants have been studied in efforts to understand protein folding and stability.61-63... 

III. Structural Determinants of Folding and Stability A. Number of Helices... 

Kwok, S. C., and Hodges, R. S. (2003). Clustering of large hydrophobes in the hydro-phobic core of two-stranded alpha-helical coiled-coils controls protein folding and stability. / Biol. Chem. 278, 35248-35254. 

Hydrophobic forces The hydrophobic effect is the name given to those forces that cause nonpolar molecules to minimize their contact with water. This is clearly seen with amphipathic molecules such as lipids and detergents which form micelles in aqueous solution (see Topic El). Proteins, too, find a conformation in which their nonpolar side chains are largely out of contact with the aqueous solvent, and thus hydrophobic forces are an important determinant of protein structure, folding and stability. In proteins, the effects of hydrophobic forces are often termed hydrophobic bonding, to indicate the specific nature of protein folding under the influence of the hydrophobic effect. 

Heinemann, U., and Hahn, M. (1995). Circular permutation of polypeptide chains implications for protein folding and stability. Prog. Biophys. Mol. Biol, 64, 121-143. 

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