Figure 1. Molten globule state. Source: Réf. 21.
Beginning of helix formation and collapse
Beginning of helix formation and collapse
placement of the unfolded protein into refolding conditions. Only after the required molten globule intermediate has been generated should N appear. However, experimental data (25) have shown that under refolding conditions the equation should be rewritten to be
The molten globule state in itself does not produce rapid folding, but has been speculated to be an off-pathway, nonproductive species that is the energetically preferred form of the unfolded protein under refolding conditions (25). Research has shown that the primary role for the molten globule state is to only slightly increase the overall rate of disulfide formation and to favor those interactions between cysteine residues distant in the polypeptide chain (26).
Physiological Role of the Molten Globule: Molecular Chap-erones and Foldases. The physiological role of the molten globule has been speculated greatly during the past few years. Because of the properties that define the molten globule, proteins in vivo must adjust themselves to a large set of different conditions, eg, in the cytoplasm and/or near membranes where a number of these conditions are denaturing ones, ie, low pH or differing salt concentrations.
The molten globule state permits proteins to exist in this state of flux, which allows for more pronounced small-scale fluctuations than the native state, which protects it from occasional loss of folding pattern by large-scale thermal fluctuations (27). The molten globule state and the newer, more expanded molten globule, the premolten globule (28), may be important for a class of proteins, chaperones, to trap proteins after their biosynthesis for self-assembly, transmembrane transport, and other processes that use protein molecules in a semiflexible (rather than in a rigid) state (27).
Molecular chaperones have been identified as a family of proteins that bind to and assist in the folding of proteins into their functional states. They do not form part of the final protein structure, nor do they possess steric information specifying a particular folding or assembly pathway (29). By recognizing unfolded or partially denatured proteins, the predominant role of chaperones seems to consist in the prevention of incorrect intra-and intermolecular associations of polypeptide chains that would result in their aggregation (30).
Consistent with their role in the folding of newly synthesized translocated proteins, many molecular chaperones are constitutively expressed. Under conditions that compromise protein folding and cell physiology, eg, heat shock, the synthesis of most molecular chaperones is induced to higher levels. It is then not surprising that many of the molecular chaperones were first identified in one or more organisms as heat shock proteins (HSPs) (31). However, it is now recognized that the same closely related proteins are frequently essential components of normal cells (30).
Chaperones themselves have aids or accessory proteins called co-chaperones that are responsible for mediating the activity of specific chaperones (32). They were first identified in Escherichia coli, and some have been shown to stimulate the rate of ATP hydrolysis (DnaJ) or act as a nucleotide exchange factor (as in the case for DnaK) (33).
The final group of protein folding helpers includes the array of proteins that act as foldases. Foldases include enzymes such as protein disulfide isomerases (PDLs) (34) and the immunophiles or peptidylprolyl isomerases (PPIs or rotamase) (35). These proteins have demonstrated catalytic activities that increase the rate of protein folding (36,37).
To perform its biological function, a protein cannot remain as a linear string of amino acids that has just come off of the protein-making ribosome. It must fold into its three-dimensional native state. The molten globule state is widely considered to be an important intermediate in protein folding and to have a polypeptide backbone with a nativelike topology. The importance of the molten globule is not in rapid protein folding, but for aiding in the trapping of the protein by molecular chaperones that assist in protein folding and targeting. The notion that chaperones are needed to assist protein folding is an interesting concept that extends rather than negates Anfinsen's findings (14) that proteins fold spontaneously based on their sequence. Although Anfinsen's findings were based on in vitro experiments, the chaperone (GroEL, in this example) appears to form a large central cavity inside its structure that allows the molten globule state protein the ability to self-assemble within the confines of the chaperone environment (38). The role of the chaperone (GroEL) is believed to be through assisting in the repeated binding and releasing of unfolded or partially folded polypeptide. During each binding interval, the chaperone sequesters the polypeptide and prevents formation of nonnative conformations. Eventually, when the protein has achieved its native state, it dissociates from the chaperone to perform its function^).
When proteins are not in their native conformation, they suffer a loss in functionality. This loss of functionality is an important aspect not only in food processes but in nature.
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