Human Peptidylprolyl Isomerase-Like 2 Isoform b

1971: Looking for antibiotics, B. Thiele, at Sandoz (now Novartis) laboratories in Switzerland,
isolated cyclosporin from the fungus Tolypocladium inflatum.

1976: J. F. Borel discovered cyclospoprin’s immunosuppressive activity.

1983: Cyclosporin was approved for clinical use to prevent graft rejection in transplantation,
including preventing graft rejection in kidney, liver, heart, lung and combined heart-lung transplants. It is used to prevent rejection following bone marrow transplantation and in the prophylaxis of host-versus-graft disease.

1997: Cyclosporin is also used in the treatment of psoriasis, atopic dermatitis,
rheumatoid arthritis, nephrotic syndrome and other immune related diseases.
2005: Cyclosporin analogs are the most important immunosuppressants.
Short-term outcomes for solid organ transplantation have been significantly benefited by cyclosporin;
however, long-term outcomes have been less effective, probably because of side effects,
and because cyclosporin therapy has not led to a reduced incidence of chronic allograft nephropathy.

The molecular mechanism of cyclosporin action is not completely understood,
but is thought to inhibit the calcium-activated serine/threonine-specific protein phosphatase
calcineurin, which dephosphorylates/activates a transcription factor that promotes expression
of T-cell-mitogenic lymphokines.
Inhibition of the phosphatase occurs through a apparently coincidental interaction
with cyclosporin-bound cyclophilin-A.
Cyclophilin-A has been shown, at least in vitro, to act as a peptidyl-prolyl cis trans isomerase,
but whose molecular functions and biological roles are unclear.
Though powerful and fast acting, cyclosporin therapy has side effects, including hypertension,
nephrotoxicity, hypertrophy of the gums and hair and susceptibility to infections.
These side effects could be caused by cross reactivity with cyclophilins other than cyclophilin-A.

There are numerous human proteins that contain cyclophilin domains,
a relatively homogenous fold with potentially significant differences in substrate specificity.
PPIL2 (cyclophilin-60) is ubiquitously expressed,
especially in kidney cells with high levels in proximal and distal-tubule cells
and collecting duct cells, but not in glomeruli.
Other cells exhibiting high expression include developing spermatozoa in the testis,
both acinar and islet cells in the pancreas, cells lining the gastric pit,
goblet cells of the colon, follicular epithelial cells of the thyroid,
prostatic epithelium and squamous cell carcinoma.
Cross reactivity of cyclosporin with PPIL2 could account for its nephrotoxic side effects.

We have determined the high-resolution crystal structure of human PPIL2
and show a fold similar to cyclophilin-A, but with variable loop lengths.
Notably, active site residues in PPIL2 that have previously been implicated in substrate specificity
are substantially different compared with cyclophilin-A.
A better understanding of how cyclosporin analogs interact with PPIL2 could lead to more specific
and more effective immunosuppressant drugs.