Biomolecules at Kenyon  HHMI at Kenyon  Jmol Home  Biology Dept  COMMENTS and CORRECTIONS

Cyclophilin B: A Prolyl Isomerase

Shante Jackson '13 and Irene McIntosh '13


I. Introduction

Cyclophilin B (CyPB) is a peptidylprolyl isomerase (PPIase).  PPIases activate the isomerization between the cis and trans conformations of amino acids during protein folding in the endoplasmic reticulum (ER). This makes CyPB (and all other PPIases) a chaperone protein, and one with a high affinity for isomerizing proline. CyPB also has a high binding affinity for cyclosporine A (CsA), an immunosuppresant that is used in the recovery of patiens who have undergone organ trsnplant surgery and aides in reducing organ rejection.

CyPB is located in the ER of cells and binds to other ER proteins to form a complex. A lectin chaperone such as calnexin contains a proline rich "P-domain" that has negatively charged aspartates and glutamates which interact with the positively charged lysines on CyPB's P-domain-interacting site. The calnexin complex folds N-glycosylated proteins by removing the N-glycan of the nitrogen terminus of a protein.

II. General Structure

The cyclophilin family of proteins have immense structural similarity, differing from A to D forms in their amino acid residues in their domains surrounding a core. 

CyPB has 8 antiparallel beta sheets that form the beta barrel . characterized by hairpin turns and hydrogen bonds between the sheets. Through the eyelet, or central opening, of this barrel is the hydrophobic core, made up of proline, asparagine, glysine, and other nonpolar residues .

There are three alpha helices that surround the barrel . Two of these (helix 2 and helix 3 ) serve to stabilize the barrel, while helix 1 is part of the CsA binding pocket.

III. P-Domain Binding

When cyclophilin is in the calnexin complex, it serves to isomerize the amino acid proline.  Proline requires a high activation energy to convert  from cis to trans conformation.  Most amino acids prefer the trans conformation when they bind to other amino acids because it's sterically beneficial, but because of proline's ring structure it can adopt the cis conformation and remain stable.

The Lys6, Lys9, Leu98, Thr36, and Ile181 residues in the p-domain interacting area attach to the negative aspartates and glutamates on P-sites of other chaperone proteins in the ER.

IV. Cyclosporine A Binding

Cyclosprine A is a peptide initially harvested from the fungus Tolypocladium inlfatum and functions as an immunosuppresant. It has a high affinity for the CyB binding site, which is opposite the P-domain binding site. When CsA is bound to CyPB, the PPIase activity of the protein is blocked. CsA inhibits helper T-cells from being synthesized when T-cell recepotors have been stimulated. The CsA enters the cell and binds to its CyPB. The CyBP-CsA complex inhibits both the enzyme responsible for activiating the creation of interleukins and the one responsible for releasing them from the T-cell.  The capacity of the T-cell to start a signal chain against antibodies is therefore reduced. How T-cells are activated. 

The CsA binding pocket is hydrophobic and polar.  Lys126 and His134 create one side of the pocket . Trp129, located on the edge of the pocket , is the main binding site for CsA. Forming the bottom and opposite side of the pocket are various residues and four beta strands

V. Conclusion

Cyclophilin B is found in most prokaryotes and eukaryotes.  All of the molecules in the cyclophilin family serve important roles in various parts of the cell.  Further research of the cyclophilin-cyclosporine complex is needed to understand it's possible use in medicinal fields.

VI. References

Allain, Fabrice, Agnes Denys, Genvieve Spik. 1994. "Characterization of surface binding sites for cyclophilin B on a human tumor T-cell line." The Journal of Biological Chemistry 269.24: 16537-16540.

Allain, Fabrice, Agnes Denys, Genvieve Spik. 1996. "Cyclophilin B mediates the cyclosporine A incorporation in human T-lymphocytes through the specific binding of complexed drug to the cell surface." Biochem Journal: 565-570.

Ke, Hemming, Lynne D. Zydowski, Jun Liu, Christopher T. Walsh. 1991. "Crystal resolution of recombinant human T-cell cyclophilin A at 2.5 Angtsrom resolution." Proc. Natl. Acad. Sci. USA 88: 9483-9487.

Kozlov, Guennadi, Sara Bastos-Aristizibal, Pekka Maattanen. 2010. "Structural basis of cyclophilin B binding by the calnexin/caltreculin P-domain." The Journal of Biological Chemistry 285.46: 35551-35557.

Mikol, Vincent, Jorg Kallen, Malcolm D. Walkinshaw. 1994. "X-ray structure of a cyclophilin B/cyclosporin complex: Comparison with cyclophilin A and delineation of its calcineurin-binding domain." Proc. Natl. Acad. Sci. USA 91:5183-5186.

Price, E. Royden, Lynne D. Zydowski, Mingjie Jin. 1991. "Human cyclophilin B: A second cyclophilin gene encodes a peptidyl-prolyl isomerase with a signal sequence." Proc. Natl. Acad. Sci. USA 88: 1903-1907.

Back to Top