Thermodynamic properties of transient intermediates and transition states in the folding of two contrasting protein structures.
The N-terminal domain of phosphoglycerate kinase (N-PGK) and domain 1 of the T-cell adhesion protein CD2 (CD2.d1) fold through rapidly formed and transiently populated intermediate states in reactions which have no kinetic complications arising from proline isomerization or disulfide bonding. We have evaluated the thermodynamic parameters (DeltaCp, change in heat capacity; DeltaS, entropy change; DeltaH, enthalpy change) for each experimentally accessible step in these folding reactions. Despite their different topologies and amino acid compositions, the individual steps [U-I (unfolded to intermediate state), I-t (intermediate to major transition state), and t-F (transition state to the fully folded state)] have closely similar qualitative properties in the two proteins. For both, the heat capacity changes are proportional to m-value changes (Deltam) for every step in the reaction, but the ratio DeltaCp/Deltam is lower for N-PGK, presumably owing to a much larger compliment of aromatic amino acids in the core. According to measurements of DeltaCp and Deltam, the I-states are highly condensed (65-70% for N-PGK and 40-45% dehydrated for CD2.d1), yet the changes in entropy in the U-to-I transition are small, showing that the entropy gained from desolvation must be balanced by that lost in ordering the chain. The high degree of conformational order in the I-state, implied by these measurements, is mirrored by the extensive, native secondary structure revealed by amide exchange measurements [Hosszu, L. L. P., et al. (1997) Nat. Struct. Biol. 4, 801-804; Parker, M. J., et al. (1997) Biochemistry 36, 13396-13405]. At 25 degreesC the transition state barrier has an entirely enthalpic origin, the entropic contribution being favorable. The latter observation implies that, during the consolidation of structure occurring in the I-to-F step, further dehydration (positive DeltaS) precedes side-chain locking (negative DeltaS). Only after the transition state is surmounted do we see a net entropic penalty arising from the widespread ordering of side chains.[1]References
- Thermodynamic properties of transient intermediates and transition states in the folding of two contrasting protein structures. Parker, M.J., Lorch, M., Sessions, R.B., Clarke, A.R. Biochemistry (1998) [Pubmed]
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