Autocatalyzed protein folding.


Abstract

Proline isomerization, an intrinsically slow process, kinetically traps intermediates in slow protein folding reactions. Thus, enzymes that catalyze proline isomerization (prolyl isomerases) often catalyze protein folding. We have investigated the folding kinetics of FKBP, a prolyl isomerase. The main conclusion is that FKBP catalyzes its own folding. Altogether, the FKBP refolding kinetics are resolved into three exponential phases: a fast phase, tau 3; an intermediate phase, tau 2; and a slow phase, tau 1. Unfolding occurs in a single phase, the unfolding branch of phase tau 2. In the presence of native FKBP, both the intermediate (tau 2) and slow (tau 1) phases are faster, suggesting that folding phases tau 1 and tau 2 involve proline cis-trans isomerization. In the absence of added native FKBP, autocatalytic folding of FKBP is detected. For refolding starting with all the FKBP unfolded initially, the slowest folding phase (tau 1) is almost 2-fold faster at a final concentration of 14 microM FKBP than at 2 microM FKBP, suggesting that catalytically active FKBP formed in the fast (tau 3) or intermediate (tau 2) folding phases catalyzes the slow folding phase (tau 1). Moreover, autocatalysis of folding is inhibited by FK506, an inhibitor of the FKBP prolyl isomerase activity. The results show that the slow phase in FKBP folding is an autocatalyzed formation of native FKBP from kinetically trapped species with non-native proline isomers. While the magnitude of the catalytic effects reported here are modest, FKBP folding may provide a prototype for autocatalysis of kinetically trapped macromolecular conformational changes in other systems. Study holds ProTherm entries: 4807 Extra Details: additive : EDTA(1 mM), proline isomerization; protein folding; folding kinetics;,autocatalysis; conformational changes

Submission Details

ID: HdSiKRxy3

Submitter: Connie Wang

Submission Date: April 24, 2018, 8:27 p.m.

Version: 1

Publication Details
Veeraraghavan S;Holzman TF;Nall BT,Biochemistry (1996) Autocatalyzed protein folding. PMID:8718848
Additional Information

Structure view and single mutant data analysis

Study data

No weblogo for data of varying length.
Colors: D E R H K S T N Q A V I L M F Y W C G P
 

Data Distribution

Studies with similar sequences (approximate matches)

Correlation with other assays (exact sequence matches)


Relevant PDB Entries

Structure ID Release Date Resolution Structure Title
1FKK 1995-08-18T00:00:00+0000 2.2 ATOMIC STRUCTURE OF FKBP12, AN IMMUNOPHILIN BINDING PROTEIN
1FKL 1995-08-18T00:00:00+0000 1.7 ATOMIC STRUCTURE OF FKBP12-RAPAYMYCIN, AN IMMUNOPHILIN-IMMUNOSUPPRESSANT COMPLEX
1TCO 1996-08-21T00:00:00+0000 2.5 TERNARY COMPLEX OF A CALCINEURIN A FRAGMENT, CALCINEURIN B, FKBP12 AND THE IMMUNOSUPPRESSANT DRUG FK506 (TACROLIMUS)
3J8H 2014-10-26T00:00:00+0000 3.8 Structure of the rabbit ryanodine receptor RyR1 in complex with FKBP12 at 3.8 Angstrom resolution
5GKY 2016-07-07T00:00:00+0000 3.8 Structure of RyR1 in a closed state (C1 conformer)
5GKZ 2016-07-07T00:00:00+0000 4.0 Structure of RyR1 in a closed state (C3 conformer)
5GL0 2016-07-07T00:00:00+0000 4.2 Structure of RyR1 in a closed state (C4 conformer)
5GL1 2016-07-07T00:00:00+0000 5.7 Structure of RyR1 in an open state
1A7X 1998-03-18T00:00:00+0000 2.0 FKBP12-FK1012 COMPLEX
1B6C 1999-01-13T00:00:00+0000 2.6 CRYSTAL STRUCTURE OF THE CYTOPLASMIC DOMAIN OF THE TYPE I TGF-BETA RECEPTOR IN COMPLEX WITH FKBP12

Relevant UniProtKB Entries

Percent Identity Matching Chains Protein Accession Entry Name
100.0 Peptidyl-prolyl cis-trans isomerase FKBP1A P62942 FKB1A_HUMAN
100.0 Peptidyl-prolyl cis-trans isomerase FKBP1A P62943 FKB1A_RABIT
97.2 Peptidyl-prolyl cis-trans isomerase FKBP1A P18203 FKB1A_BOVIN
97.2 Peptidyl-prolyl cis-trans isomerase FKBP1A P26883 FKB1A_MOUSE
97.2 Peptidyl-prolyl cis-trans isomerase FKBP1A Q62658 FKB1A_RAT