Cyclophilin human

Kallen, J., et al. Structure of human cyclophilin and its binding site for cyclosporin A determined by x-ray crystallography and NMR spectroscopy. Nature 353 276-279, 1991. 

Fig. 11 Separation of human cyclophilin 18 (1) and the corresponding complex with the immunosuppressant cyclosporin A (2) by CE. A fixed concentration of cyclophilin (6.1 /xM) and increasing concentrations of cyclosporin (0 /xM, A, 2 /xM, B, 4 /xM, C, 7 /xM CsA, D) dissolved in DMSO (3) were incubated prior to the CE separation. (Reprinted with permission from Ref. 42. Copyright 1999 of Elsevier Science.)...

L. Demange, M. Moutiez, K. Vaudry, C. Dugave, Interaction of human cyclophilin hCyp-18 with short peptides suggests the existence of two functionally independent subsites, FEBS Lett. 505 (2001) 191-195. 

Since its introduction into clinical use in about 1979 the immunosuppresant cyclosporin has been responsible for a revolution in human organ transplantation.3 The exact mechanism of action in suppressing T-lymphocyte-mediated autoimmune responses is still not completely clear, but cyclosporin, a cyclic lipophilic peptide from a fungus, was found to bind to specific proteins that were named cydophilins.d Human cyclophilin A is a 165-residue protein which associates, in the crystal form, as a decamer with five-fold rotational and dihedral symmetry.6 This protein is also found in almost all... 

Cyclosporin (black) bound to human cyclophilin. From Pfluglef aZ.e Courtesy of J. N. Jansonius. 

Cyclohexanedione, reaction with guanidinium groups, 126 Cyclophilin 488 human 488s D-Cycloserine 739s Cyclosporin 488, 488s p Cylinders 65, 66, 686 Cystathionine, 746s formation 746 Cystathionine p lyase 742 Cystathionine p-synthase 744 Cystathionine y-synthase 743, 746 Cystatins 622, 629... 

Fig. 2. Ribbon plot of the overall fold of human cyclophilin. The complex with the tetrapeptide substrate A -acetyl-Ala-Ala-Pro-Ala-amidomethylcoumarin is shown. From Kallen et al. (1991). Reprinted by permission from Nature 353, 276. Copyright 1991 Macmillan Magazines Ltd.

The amino acid sequences of the cyclophilins remained highly conserved during evolution. This holds in particular for the proteins from eukaryotes. The cyclophilins from bovine thymus and from porcine kidney are identical in sequence (Takahashi et al., 1989), and the human and the bovine cyclophilins share 98% identical amino acids (Haendler et al., 1987). The homology between the mammalian cyclophilins and the cytosolic PPl from E. coli is about 25% (Hayano et al., 1991). The PPIs from porcine kidney and E. coli cytoplasm were used in most of the work on the function of prolyl isomerases as catalysts of protein folding that will be discussed herein. 

Note Added in Proof. The structure of free prolyl isomerases of the cyclophilin type was rehned at 1.63 A (Ke, 1992). Further work on the complex of human cyclophilin with a tetrapeptide showed that the peptide N-acetyl-Ala-Ala-Pro-Ala-amidomethylcoumarin... 

Yin, L., Braaten, D. and Luban, J. (1998) Human irrrmunodeficiency virus type 1 replication is modulated by host cyclophilin A expression levels. J. Virol. 72, 6430-6436. 

Liu, J., Chen, C. M., and Walsh, C. T., Human and Escherichia coli cyclophilins Sensitivity to inhibition by the immunosuppressant cyclosporin A correlates with a specific tryptophan residue, Biochemisty, 30(9], 2306, 1991. 

A schematic representation of the diverse group of human cyclophilins is given in Fig. 10.1. 

FKBP 12 and CyPA are the prototypical members of two large families of rotamases.82 The residues which comprise the rotamase do-main/FK506 binding site of human FKBP 12, and the rotamase do-main/CsA binding site of CyPA, define respectively an FKBP domain and cyclophilin domain which are remarkably conserved in the higher molecular weight family members and across species. Table 2 summarizes the conservation of these two domains in the immunophilins listed in Table 1. The three-dimensional structure of these immunophilin domains will be discussed in the next section. 

Table 2. Conservation of Immunophilin Domains in Human FKBPs and Cyclophilins... 

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