Preface [Hot Topic: Immunophilins - The Long and Winding Road (Guest Editor: Michael Ivery)].

For proteins that are found in organisms ranging from bacteria to humans the clear delineation of the cellular function of immunophilins has run a tortuous path which in some ways appears little closer to its final destination. (Galat pp 1315-1349) This journey has been marked by many waypoints along the road that at each stage has given rise to a new nomenclature for these ubiquitous proteins. The scientific odyssey began in 1984 with the description of porcine peptidyl-prolyl isomerase (PPIase) an enzyme identified as capable of catalysing the cis-trans isomerization of peptidyl-prolyl bonds which was proposed as a rate-limiting step in protein folding. However, it is only recently that the importance of PPIase enzymes in protein folding in vivo has been demonstrated with the identification of a number of PPIase enzymes as crucial members of steroid receptor complexes. (Ratajczak pp 1351-1361)A second journey for investigators of PPIases began from a seemingly different starting point with the discovery that the macromolecular target for the immunosuppressant natural product cyclosporin A termed cyclophilin A (CsA) was identical to porcine peptidyl-prolyl isomerase. Subsequently a second enzyme known as FKBP12, also possessing PPIase activity was identified as the target for a second immunosuppressant natural product FK506 and this lead to the PPIase enzymes being referred to as immunophilins, a classification for enzymes that contain both PPIase activity and bind natural product immunosuppressant drugs. Both FK506 and CsA potently inhibit the PPIase activity of their respective immunophilin protein partners, however, the initial hope that somehow the PPIase activity of these compounds was involved in the immune response was soon dashed with the development of potent PPIase activity inhibitors that possessed no immunosuppression activity. Remarkably, despite their structural diversity both CsA and FK506 mediate their biological effects through inhibition of the same protein phosphatase calcineurin (CN) and inhibition of PPIase activity was found to be ancillary to the immunosuupressant effects. Recently this story has taken a new twist with the proposal that immunophilin drug-complexes block additional signal transduction pathways in activated ‘T’ cells and that these T-cell specific pathways maybe a significant contributor to the source of the T-cell specific effects of these compounds (Koyasu pp 1363-1373)At this point a third journey which is still progressing began with the realisation that immunophilins co-localise with calcineurin and as such are expressed at very high levels within the brain. Subsequent studies in animal models of nerve damage identified FK506 and to a lesser extent CsA as potent neuroprotective and neuroregenerative agents. However, this trip did not converge on the same destination (calcineurin) as immunosuppression with non-immunosuppressant immunophilin ligands being found to be equally neurotrophic as FK506. Recent studies have suggested that a specific FKBP protein (FKBP52) is largely the target responsible for these effects, with binding of FKBP52 disrupting steroid hormone receptor complexes leading to activation of specific signal transduction pathways. (Gold pp 1375-1383) However even these results are becoming more complicated by the day with the discovery that several immunophilins associate with the steroid receptor including both FKBP and cyclophilin classes and that specific steroid receptors appear to have preferences for specific immunophilins. Additionally recent studies on protein composition within brain lesions indicate that FKBP12 is overexpressed in a range protein aggregation events characterising a range neurodegenerative diseases. (Achim pp 1385-1391)In each of the above journeys a common feature appears to be the ability of immunophilins to facilitate the association of proteins or to stabilise protein-protein complexes. This hypothesis is further supported by recent studies indicate that immunophilins are involved in a range of other protein-protein complexes including calcium induced calcium release channels (Marks pp 1393-1402), interactions with the TGF-β receptor and HIV Gag protein. In many of these cases substantial structural characterisation has been achieved with more than 100 crystal structures for immunophilin and immunophilin-protein complexes having being determined. (Walkinshaw pp 1403-1425). The role of immunophilins in all of these complexes is not clear with a defined function for their PPIase activity generally difficult to establish but in each case ligands targeting the immunophilin either stabilise a protein-protein complex (immunosuppression) or destabilise the complex (calcium channels, steroid receptor). Within this issue we present a collection of reviews examining the breadth of the many functions exhibited by immunophilin / neurophilin enzymes and