Cyclophilin families

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... 

A gene product specific for natural killer cells in mice and humans has been characterized as a PPIase of the cyclophilin family.59 CyP-NK appears to be important in NK-cell cytotoxicity. This multiple domain protein contains a large hydrophobic domain in the N-terminus followed... 

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... 

The periplasm of E. coli contains prolyl isomerases of all three families. PPIA is a member of the cyclophilin family (Liu and Walsh, 1990 Hayano et al., 1991), FkpA or FKBP26 (Horne and Young, 1995) contains a FKBP12-like domain, and SurA (Rouviere and Gross, 1996) and PpiD (Dartigalongue and Raina, 1998) show parvulin domains. SurA is a soluble protein, whereas PpiD is attached to the inner membrane with its catalytic domain exposed to the periplasmic space. 

Immunophilin is the generic term for a binding protein for an immunosuppressive agent, and all currently known immunophilins belong to the cyclophilin or FKBP families. The two families of immunophilins— like the small molecules they bind—don t have any readily apparent relationship. FKBP12 and CyPA have no sequence similarity, CsA does not inhibit FKBP12, and FK506 does not inhibit CyPA. 

The smallest member of a new family of prolyl iso-merases (unrelated to the cyclophilins or the FK-506 binding proteins) that catalyzes the proline-limited folding of a variant of ribonuclease T1 with a KJK value of 30,000 M s With the tetrapeptide succinyl-Ala-Leu-Pro-Phe-4-nitroanilide as a substrate in parvulin-catalyzed prolyl isomerization, this parameter is 1.1 x 10 M s Parvulin also accelerates its own refolding in an autocatalytic fashion. 

Another drug whose immunosuppressive action is mediated by the complexation with a cellular protein of the immunophilins is FK506. FK506 binds to proteins of the FKBP family. The complex formed is involved in the inhibition of the phosphatase calcineurin, similar to the mode of action of CsA after binding to cyclophilin. The ACE method was used to detect... 

Cyclophilins and FKBPs are large families of proteins. In E. coli there are two cyclophilin genes, three encoding FK506-binding proteins, and one of... 

Protein family PDI Cyclophilin PPIase FKBP PPIase Hsp60 Hsp70 Hsp90... 

We will use the term PPI when the enzymatic activity as prolyl isomerase is concerned, and the terms cyclophilin and FKBP to discriminate the two known families of prolyl isomerases that are inhibited by CsA and by FK506, respectively. Cyclophilin and FKBP differ strongly in sequence specificity. The PPI activity of cyclophilin shows only a small dependence on the chemical nature of the amino acid Xaa that precedes proline in the assay peptide. The activity of FKBP, however, varies by three orders of magnitude when the same set of peptides is used in the PPI assays (Harrison and Stein, 1990 see Stein, this volume). 

Proteins homologous to the cytosolic cyclophilins from vertebrates or the corresponding genes are found virtually in every organism and in every subcellular compartment. All members of this family that could be obtained in purified form had a high prolyl isomerase activity and were inhibited by CsA, albeit with different effectiveness. Notably, the affinity... 

Formerly DUPDl, but does not contain an N-terminal cyclophilin domain, as originally annotated. The mouse ortholog also lacks cyclophilin domain. Thus, the name DUPDl is a misnomer hjumpy lacks any of the typical domains characteristic of the myotubularin family, but it does contain the myotubularin-specif WDR motif within the P loop and does have phosphatidylinositol-... 

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. 

Prolyl isomerases belong to three structurally diverse families the cyclophilins, the FK506 binding proteins, and the parvulins. Usually, they are abbreviated to Cyp, FKBP and Parv, followed by the molecular mass and, sometimes, an indicator for the subcellular localization. Cypl8cy thus denotes the cytoplasmic cyclophilin with a molecular mass of 18 kDa. This cyclophilin is also often referred to as CypA. 

Harrison, R. K., and Stein, R. L. (1990). Substrate specificities of the peptidyl prolyl cis-trans isomerase activities of cyclophilin and FK506-binding protein Evidence for the existence of a family of distinct enzymes. Biochemistry 29, 3813-3816. 

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