The FKBP and Cyclophilin Families

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. 

Of the 13 residues that define the FKBP domain motif, 10 are highly conserved, and 7 (Tyr-26, Phe-36, Asp-37, Val-55, Ile-56, Tyr-82, and Phe-99) are completely conserved in all FKBPs, from all species, that possess significant rotamase activity. The position of greatest variability is His-87, which is replaced in other FKBPs by various hydrophilic or hydrophobic residues. Replacement of Phe-46 by other hydrophobic residues has little effect on rotamase activity. 

Two new immunophilins have recently been discovered which contain both FKBP and cyclophilin domains. A 37 kDa protein isolated from the Jurkat T-cell line was found to bind FK506, rapamycin, and cyclosporin A, all with high affinity.50 FKBP37 contains two FKBP domains and one cyclophilin domain, and also possesses glyceraldehyde 3-phosphate dehydrogenase activity. The 52 kDa protein, isolated from human lymphoid cells, also binds all three immunosuppressant drugs but shows no detectable rotamase activity towards a variety of peptidic substrates.95 

The cyclophilin rotamase domain is very highly conserved in the cyclophilin family. As shown in Table 2, cyclophilins A-D all have identical CyP domains. Human cyclophilin B, which is localized to the endoplasmic reticulum, contains an ER-directed sequence. Comparison 

Cyclophilin C was first characterized in the rat, where it was observed to be expressed in a smaller subset of tissues than was CyPA or CyPB.22 In humans CyPC is abundant in the kidney, pancreas, skeletal muscle, heart, lung, and liver, but is almost absent from T-cells and the brain.56 CyPC binds CsA with an affinity comparable to that of CyPA. It also binds a 77 kDa glycoprotein, called cyclophilin-C-associated-protein (CypCAP) in the absence of CsA, which is a competitive inhibitor of this interaction.22,99 The physiological relevance of the CyPC-CypCAP interaction is not known. 

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In the 15 years since the discovery of cyclophilin there has been an enormous proliferation of known peptidylprolyl isomerases. The members of the FKBP and cyclophilin families, known collectively as the... 

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