Abstract:
:Unfolded RNase A is known to contain an equilibrium mixture of two forms, a slow-folding form (U(1)) and a fast-folding form (U(2)). If U(1) is produced after unfolding by the slow cis-trans isomerization of proline residues about X-Pro imide bonds, then the formation of U(1) should be catalyzed by strong acids. Therefore, the rate of formation of U(1) has been measured at different HClO(4) concentrations. After rapid unfolding of the native protein in concentrated HClO(4) at 0 degrees , the slow formation of U(1) was measured by use of refolding assays. Catalysis of its formation was found at HClO(4) concentrations above 5 M. The uncatalyzed reaction follows apparent first-order kinetics but, in the acid-catalyzed range, two reactions are found. The faster reaction produces two-thirds of the slow-folding species and shows acid catalysis above 5 M HClO(4). Catalysis of the slower reaction begins at 8 M HClO(4). The faster reaction shows a 100-fold increase in rate at 10.6 M HClO(4) over the rate of the uncatalyzed reaction of 5 M. The activation enthalpy of the uncatalyzed reaction has been measured in two sets of unfolding conditions: DeltaH(double dagger) is 21.5 kcal/mol (1 kcal = 4.2 x 10(3) J) in 3.3 M HClO(4) and 21.0 kcal/mol in 5 M guanidine HCl, pH 2.5.Both acid catalysis of the formation of U(1) and its high activation enthalpy are consistent with the rate-limiting step being cis-trans isomerization either of X-Pro imide bonds or of peptide bond. The rate of the uncatalyzed reaction is in the range expected for proline isomerization and is 0.1% of that of peptide bond isomerization; thus, the simplest explanation for the formation of U(1) is proline isomerization. Earlier data, showing that the kinetic properties of the U(1) right arrow over left arrow U(2) reaction in refolding conditions differ from those of proline isomerization, can be explained if there is kinetic coupling between early steps in the folding of U(1) and its conversion to U(2).The existence of two acid-catalyzed reactions that are distinguished by the HClO(4) concentration at which catalysis begins suggests that at least two essential proline residues produce slow-folding species of RNase A by isomerization after unfolding. Because protonation of imide bonds is responsible for acid catalysis of proline isomerization, the slower reaction probably involves an imide bond with a low pK. It may be the bond connecting Lys-41 and Pro-42, because the positive charge on Lys-41 could make this bond more difficult to protonate.
journal_name
Proc Natl Acad Sci U S Aauthors
Schmid FX,Baldwin RLdoi
10.1073/pnas.75.10.4764subject
Has Abstractpub_date
1978-10-01 00:00:00pages
4764-8issue
10eissn
0027-8424issn
1091-6490journal_volume
75pub_type
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