Functional unfolded proteins

For folded proteins, relaxation data are commonly interpreted within the framework of the model-free formalism, in which the dynamics are described by an overall rotational correlation time rm, an internal correlation time xe, and an order parameter. S 2 describing the amplitude of the internal motions (Lipari and Szabo, 1982a,b). Model-free analysis is popular because it describes molecular motions in terms of a set of intuitive physical parameters. However, the underlying assumptions of model-free analysis—that the molecule tumbles with a single isotropic correlation time and that internal motions are very much faster than overall tumbling—are of questionable validity for unfolded or partly folded proteins. Nevertheless, qualitative insights into the dynamics of unfolded states can be obtained by model-free analysis (Alexandrescu and Shortle, 1994 Buck etal., 1996 Farrow etal., 1995a). An extension of the model-free analysis to incorporate a spectral density function that assumes a distribution of correlation times on the nanosecond time scale has recently been reported (Buevich et al., 2001 Buevich and Baum, 1999) and better fits the experimental 15N relaxation data for an unfolded protein than does the conventional model-free approach. 

PMP-22 gene (Ch. 38). Because the function of PMP-22 is uncertain, the mechanisms by which the point mutations in this protein cause the trembler phenotype are unclear. However, as with the PLP mutations, the pathology may result from an unfolded protein response to abnormal protein that is retained in the endoplasmic reticulum. 

Travers, K. J., Path, C. K., Wodicka, L, Lockhart, D. J., Weissman, J. S., and Walter, P. Functional and genomic analyses reveal an essential coordination between the unfolded protein response and ER-associated degradation. Cell 2000, 101, 249-58. 

Linear Fe3S4(SR)4 clusters have been found in partially unfolded proteins, but are not known to exist as functional centers to date. Synthetic analogs comprise the all-ferric [Fe3S4(SPh)4] species (a [Fe3S4] + core) that may be reduced to the corresponding [Fe3 S4] core at —1.35 V versus SCE in acetonitrile (—1.66 V for the ethyl thiolate derivative). 

ER function, as can external agents such as calcium ionophores and chemical toxicants (Rao, et al., 2001) which can cause ER stress. ER responds to stress by triggering a specific signalling pathway termed the unfolded protein response (UPR). The UPR serves to protect the cell from normal variations that occur in the cellular environment (Ma, et al., 2004, Rao, et al., 2001). Recent evidence suggests that the UPR can also be activated in tumours (Ma, et al., 2004). 

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