Prolyl cis-trans isomerase (FKBP-type)

 

FK506 binding protein (FKBP) is a small globular protein which catalyses the isomerisation of proline cis-trans bonds in short, unstructured peptides. The protein is an immunophilin which in humans binds the cyclic lactone peptide Tacrolimus (or FK506) which results in immune response suppression, mainly through reducing the expression of interleukin 2 by T cells.

 

Reference Protein and Structure

Sequence
P62942 UniProt (5.2.1.8) IPR023566 (Sequence Homologues) (PDB Homologues)
Biological species
Homo sapiens (Human) Uniprot
PDB
1d6o - NATIVE FKBP (1.85 Å) PDBe PDBsum 1d6o
Catalytic CATH Domains
3.10.50.40 CATHdb (see all for 1d6o)
Click To Show Structure

Enzyme Reaction (EC:5.2.1.8)

peptidylproline (omega=180) residue
CHEBI:83834ChEBI
→
peptidylproline (omega=0) residue
CHEBI:83833ChEBI
Alternative enzyme names: PPIase, Cyclophilin, Peptide bond isomerase, Peptidyl-prolyl cis-trans isomerase, Rotamase, Peptidylprolyl cis-trans isomerase,

Enzyme Mechanism

Introduction

Some evidence suggests the enzyme to play a stoichiometric role, rather than an enzymatic catalytic role in vivo. The enzyme has been shown to auto-catalyse protein folding in a reversible manner, unlike the related prolyl isomerase Cyclophilin A. The non-polar active site is thought to drive isomerisation, without acid/base catalysis, by firstly directing a high energy conformation around the proline bond and secondly providing stability to the transition state, as supported by isotope labelling studies and pH dependence tests. The enzyme first induces a reaction conformation of the peptide and second stabilises the transition state of the isomerisation of peptidylproline omega=180 to peptidylproline omega=0.

Catalytic Residues Roles

UniProt PDB* (1d6o)
Phe100, Tyr27, Phe37, Tyr83, Asp38, Ile57 (main-N) Phe99A, Tyr26A, Phe36A, Tyr82A, Asp37A, Ile56A (main-N) Forms the correct steric and electrochemical environment for the rotation reaction to occur. electrostatic destabiliser, steric role, polar/non-polar interaction
*PDB label guide - RESx(y)B(C) - RES: Residue Name; x: Residue ID in PDB file; y: Residue ID in PDB sequence if different from PDB file; B: PDB Chain; C: Biological Assembly Chain if different from PDB. If label is "Not Found" it means this residue is not found in the reference PDB.

Chemical Components

isomerisation reaction (not covered by named reactions), overall reactant used, overall product formed

References

  1. Vogtherr M et al. (2002), J Mol Biol, 318, 1097-1115. NMR Solution Structure and Dynamics of the Peptidyl-prolyl cis–trans Isomerase Domain of the Trigger Factor from Mycoplasma genitalium Compared to FK506-binding Protein. DOI:10.1016/s0022-2836(02)00112-2. PMID:12054805.
  2. Tradler T et al. (1997), FEBS Lett, 407, 184-190. Comparative mutational analysis of peptidyl prolylcis/transisomerases: active sites ofEscherichia colitrigger factor and human FKBP12. DOI:10.1016/s0014-5793(97)00345-1. PMID:9166896.

Step 1. The enzyme first induces a reaction conformation of the peptide and second stabilises the transition state of the isomerisation of peptidylproline omega=180 to peptidylproline omega=0.

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Catalytic Residues Roles

Residue Roles
Asp37A steric role
Ile56A (main-N) steric role
Tyr82A steric role
Asp37A electrostatic stabiliser
Ile56A (main-N) electrostatic stabiliser
Tyr82A electrostatic stabiliser
Phe99A steric role, polar/non-polar interaction, electrostatic destabiliser
Phe36A polar/non-polar interaction, steric role, electrostatic destabiliser
Tyr26A steric role, electrostatic destabiliser

Chemical Components

isomerisation reaction (not covered by named reactions), overall reactant used, overall product formed

Step 1. The enzyme first induces a reaction conformation of the peptide and second stabilises the transition state of the isomerisation of peptidylproline omega=180 to peptidylproline omega=0.

Contributors

Sophie T. Williams, Craig Porter, Gemma L. Holliday