Protein Folding and Protein Association

Abstract

The biosynthesis of proteins leads to linear chain1 molecules with a well-defined amino acid sequence that is unambiguously determined by a corresponding polynucleotide sequence at the level of the gene. The underlying mechanism of transcription and translation is based upon the complementarity of pyrimidine and purine bases, on the one hand, and the genetic code, on the other. As indicated by denaturationhenaturation experiments, the one-dimensional structural information encoded in the polypeptide chain generates a unique three-dimensional structure. In consequence, one would expect a "folding code" to exist which governs the spontaneous acquisition of the therrnodynamically stable "native" structure of a given protein. The rate of folding (in vivo as well as in vitro) is fast, despite the astronomically high number of potential conformations. Tlhe mechanism of folding must therefore be kinetically controlled. Whether the native structure represents the "global" or a "local" minimum on the energy hyperspace is an open question. Above a critical size, protein molecules tend to be organized as assemblies made up of identical or non-identical subunits. The observed uniformity of a given "quaternary structure" requires a close correlation of folding and association as well as a high specificity of subunit recognition. Both are corroborated by in vitro reconstitution experiments.

Disruption of the aldolase A tetramer into catalytically active monomers.

“…This is supported by the coordinate dissociation, unfolding, and inactivation observed for aldolase at extremes of pH (36). Furthermore, direct evidence that quaternary structure provides stability was shown by monomeric aldolase with increased susceptibility to urea-induced inactivation compared to the same mutant tetrameric enzyme (Fig.…”

Do metal ions promote the re-activation of the 2,3-bisphosphoglycerate-independent phosphoglycerate mutases?

“…6) may be a consequence of the size of the polypeptide chain. Other work (Jaenicke, 1984;Teschner et al, 1987) has shown that polypeptide chains more than about 300 amino acids in length often refold very slowly and/or inefficiently because of the failure to co-ordinate the processes of chain folding and domain pairing.…”

“…It has been shown that the rate of re-activation of many large polypeptide chains (> 300 amino acids) is slow and often inefficient, owing to improper pairing of domains (Jaenicke, 1984;Teschner et al, 1987). The Mr of the monomeric wheat-germ enzyme is approx.…”

Mechanisms of protein stabilization in the solid state

“…27,28 Noncovalent aggregation describes association where the partially denatured protein molecules associate inter-molecularly via hydrophobic interactions in order to minimize the unfavorable exposure of hydrophobic amino acid residues to water. 29 Covalent aggregation of proteins is actually a chemical change, which involves the formation of new bonds. Thus, although sometimes categorized as a physical degradation reaction, it would be more appropriate to categorize covalent aggregation as chemical instability (section below) rather than physical instability of the protein.…”