Summary
Cis-trans isomerization in proline is a unique phenomenon arising from the cyclic nature of the pyrrolidine side chain. Unlike other amino acids where trans is favored 1000:1, proline has a significant cis population (10-30%). This isomerization is often the rate-limiting step in protein folding.
Key Points
- 1Proline cis population is 10-30% (vs 0.1% for other residues)
- 2Isomerization has high activation barrier (~20 kcal/mol)
- 3Often rate-limiting step in protein folding
- 4Catalyzed by PPIases: Cyclophilins, FKBPs, Parvulins
Proline is unique among the 20 standard amino acids, and its distinctive chemistry has profound implications for protein structure and folding kinetics.
The Proline Difference
Unlike other amino acids, proline's side chain forms a cyclic pyrrolidine ring that connects back to the backbone nitrogen. This cyclic structure has two major consequences:
Isomer Populations
While most peptide bonds favor trans by approximately 1000:1, proline-preceding peptide bonds show:
- Trans isomer: 70-90% population
- Cis isomer: 10-30% population in unfolded states
This significant cis population arises because the steric clash that normally disfavors cis is partially offset by the cyclic side chain.
Kinetic Implications
The high activation energy barrier for cis-trans interconversion (~20 kcal/mol) makes spontaneous isomerization slow (seconds to minutes). This has critical implications:
- Often acts as the rate-limiting step in protein folding
Peptidyl-Prolyl Isomerases (PPIases)
Cells have evolved specialized enzymes to accelerate proline isomerization:
- Cyclophilins: Target of the immunosuppressant cyclosporine
- FKBPs (FK506-Binding Proteins): Target of FK506/tacrolimus
- Parvulins: Including the critical signaling enzyme Pin1
Structural Roles
*Cis*-prolines are not random occurrences—they serve specific structural functions:
- Essential for Type VI β-turns
- Found in Polyproline I (PPI) helices