Molten globule state

A number of proteins are known to pass through a transient intermediate state, the so-called molten globule state. The precise stmctural features of this state are not known, but appear to be compact, and contain most of the regular stmcture of the folded protein, yet have a large side-chain disorder (9). 

V Daggett, M Levitt. A model of the molten globule state from molecular dynamics simulations. Pi-oc Natl Acad Sci USA 89 5142-5146, 1992. 

Figure 6.2 The molten globule state is an important intermediate in the folding pathway when a polypeptide chain converts from an unfolded to a folded state. The molten globule has most of the secondary structure of the native state but it is less compact and the proper packing interactions in the interior of the protein have not been formed.

An example of the use of chemical shifts to delineate residual secondary structure is given in Figure 3 for the molten globule state of apomyo-globin (Eliezer et al., 1998 Eliezer et al., 2000). Combined use of 13C , H , 13C, and 13CO secondary shifts gives a more precise definition of secondary structure boundaries than use of 13C shifts alone (Eliezer et al., 2000). 

Staniforth, R. A., Giannini, S., Higgins, L. D., Conroy, M. J., Hounslow, A. M.,Jerala, R., Craven, C. J., and Waltho, J. P. (2001). Three-dimensional domain swapping in the folded and molten-globule states of cystatins, an amyloid-forming structural superfamily. EMBO J. 20, 4774-4781. 

Kuwajima K. The molten globule state as a clue for understanding the folding and coop-erativity of globular-protein structure. Proteins (1989) 6 87-103. 

The chemical shift dispersion (Table 1) and the temperature dependence of the resonance hne shape provides a qualitative measure of whether the structure is well ordered [2]. However, NMR spectroscopy also provides information relevant to the problem of protein folding in the study of the molten globule states. NMR spectroscopic investigations of molten globules may be more demanding than those of ordered proteins due to spectral overlap arising from poor shift dispersion and to short relaxation times that are due to conformational exchange at intermediate rates on the NMR time scale. 

Significant improvements in the appearance of the NMR spectrum of molten globule states are, however, observed upon addition of small amounts of trifluoroethanol (TFE), less than 10 vol%. Amide proton exchange rates are reduced and resonances are sharpened although the chemical shift dispersion is also decreased [51]. The net result is an increased resolution that simphfies considerably the spectral assignment. The increased spectral resolution is in fact due to the fact that the peptides become more denatured rather than more structured and that, in order to obtain more structural information about the folded state, the peptide is partially unfolded ... 

Dickinson, E., Matsumura, Y. (1994). Proteins at liquid interfaces role of the molten globule state. Colloids and Surfaces B Biointerfaces, 3, 1-17. 

Kuwajima, K. and Arai, M. 2000. The molten globule state The physical picture and biological significance. In Mechanisms of Protein Folding (R.H. Pain, ed.) pp. 138-174. Oxford University Press, Oxford. 

Fig. 7.6. Figure 7.6. Backscattered ICP Raman (IR f IL) ancj j oA (IR - IL) spectra of (a) human lysozyme in the native state, (b) human lysozyme in the low pH molten globule state, and (c) the T-A-l peptide from wheat glutenin. Adapted from references 45 and 46...

Uversky, V.N., S. Winter, and G. Lober. 1996. Use of fluorescence decay times of 8-ANS-protein complexes to study the conformational transitions in proteins which unfold through the molten globule state. Biophys. Chem. 60(3) 79-88. 

Even though it was reported earlier (Dolgikh et al., 1985) that the molten globule state had a heat capacity similar to that of the unfolded state, implying that the molten globule was fully exposed to water, this view appears to be at odds with thermodynamic considerations and new experimental data. Also, if the molten globule is fully hydrated and its tertiary structure interactions are largely disrupted, why does it assume a compact conformation What are the forces... 

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