Molecular characteristics of cyclophilin-cyclosporine interaction.
The ability of cyclophilin to react with derivatives of cyclosporine (CsA) was studied. Cyclophilin was found to interact preferentially with CsA-residues 1, 2, 10 and 11, which, together with residue 3, are the residues known to contribute to the immunosuppressive activity of CsA. The recognition of different CsA-derivatives by cyclophilin was correlated with their immunosuppressive activity in vitro. All CsA-derivatives showing a significant activity did bind to cyclophilin, although some of the CsA-derivatives able to bind cyclophilin exhibited only low activities. The results suggest that binding to cyclophilin might be one requirement for immunosuppressive activity of CsA derivatives. When tested with CsA-derivatives showing various conformational changes, the binding of cyclophilin was strongly specific for the peptide-ring conformation of CsA. No binding of calmodulin to CsA could be detected in several formats of solid-phase enzyme- or radioimmunoassay, suggesting that, in contrast to cyclophilin, calmodulin does not possess sufficient affinity for CsA to bind to it when immobilized on the solid phase.
Quesniaux
V F
VF
Institut de Biologie Moléculaire et Cellulaire du CNRS, Strasbourg, France.
Schreier
M H
MH
Wenger
R M
RM
Hiestand
P C
PC
Harding
M W
MW
Van Regenmortel
M H
MH
D002147:Calmodulin / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D003524:Cyclosporins / Q000378:metabolism* / Q000494:pharmacology; D007165:Immunosuppression Therapy; D066298:In Vitro Techniques; D008213:Lymphocyte Activation / Q000187:drug effects; D007959:Lymphocyte Culture Test, Mixed; D019696:Peptidylprolyl Isomerase; D011485:Protein Binding; D013329:Structure-Activity Relationship
D002147:Calmodulin; D002352:Carrier Proteins; D003524:Cyclosporins; D019696:Peptidylprolyl Isomerase