In vivo folding

The enormous structural diversity of proteins begins with different amino acid sequences (primary structure) of polypeptide chains that fold into complex 3D structures. The final folded arrangement of the polypeptide chain is referred to as its conformation (secondary and tertiary structures). It appears that the information for folding to the native conformation is present in the amino acid sequences (Anfinsen, 1973) however, a special class of proteins known as chaperons is required to facilitate in vivo folding of a protein to form its native conformation (Martin and Hartl, 1997). 

The first basic tenet of protein-structure prediction is that the amino acid sequence, the primary structure, contains all of the information required for the correct folding of the polymer chain. This is a first approximation which clearly ignores the role of environment on the induction of structure or the action of chaperone proteins which assist the in vivo folding process. The wide variety of structural motifs that have been observed for proteins is derived from only twenty different monomers (amino acids), many of which are structurally quite similar (i.e., isoleucine and leucine vary only in branching of the butyl side chain). However, there are many cases in which the substitution of amino acids with structurally similar residues (so-called conservative substitution) will lead to a protein that will not properly fold. Studies involving deletion of even small portions of the termini of the protein sequence provide similar results. On the other hand there are proteins related through evolution with as little as 20% sequence identity which adopt similar three-dimensional structures. Therefore the information encoded in the primary sequence is specific for one protein fold, however, there are numerous other sequences, only remotely related at first glance, which will produce the same fold. 

Prolyl isomerases of the cyclophilin type show some properties that would be expected for a catalyst of cellular protein folding. Cyclophilins occur in all cellular compartments where folding reactions occur. The activity toward accessible prolyl bonds is high, and the specificity with regard to the chemical nature of residue Xaa is low. Additional experiments are clearly needed, however, to clarify the possible role of prolyl isomerases for the in vivo folding process of nascent proteins. 

Noorwez SM, Kuksa V, Imanishi Y, Zhu L, FUipek S, Pal-czewski K, Kaushal S. Pharmacological chaperone-mediated in vivo folding and stabilization of the P23H-opsin mntant associated with autosomal dominant retinitis pigmentosa. J. Biol. Chem. 2003 278 14442-14450. 

The folding of proteins in the cell proceeds under conditions markedly different from those employed in refolding studies. Although little conclusive information is available it is generally thought that the in-vivo folding pathway is directly affected by the synthesis, covalent modification and localization of die polypeptide chain. 

However, during the in vivo folding process, the polypeptide chain passes through... 

Thermal Unfolding Pathway Differs from the in vivo Folding Pathway... 

In any case, the difference between the in vivo folding pathway and the in vitro thermal unfolding pathway indicates the importance of kinetic aspects in controlling the folding and unfolding of this protein. 

Winklhofer KF, Heske J, Heller U, Reintjes A, Muranyi W, Moarefi I, Tatzelt J (2003) Determinants of the in vivo folding of the prion protein - a bipartite function of helix 1 in folding and aggregation. J Biol Chem 278 14961... 

D. Thirumalai, Theoretical perspectives on in vitro and in vivo folding, in S. Doniach, editor. Statistical Mechanics, Protein Structure, and Protein ubstrate Interactions, Plenum, New York, 1994, pp. 115-134. 

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