Immunophilins consist of a family of highly conserved
proteins binding with immunosuppressive drugs such as
FK506,
rapamycin and
cyclosporin A.
FK506-binding protein (
FKBP) is one of two major
immunophilins and most of
FKBP family members bind
FK506 and show peptidylprolyl
cis/trans isomerase (
PPIase) activity. Small size
FKBP family members contain only FK506-binding domain, while FKBPs with large molecular weights possess extra domains such as tetratricopeptide repeat domains,
calmodulin binding and transmembrane motifs. FKBPs are involved in several biochemical processes including protein folding, receptor signaling, protein trafficking and transcription.
FKBP family
proteins play important functional roles in the T-cell activation, when complexed with their
ligands. The roles of
immunophilins in
protein transportation and apoptosis through their molecular interactions with receptors or
proteins have emerged recently. Moreover, therapeutic implications of
immunophilin ligands in treating
neurodegenerative disorders have been accumulating.
FK506 and its derivatives with no immunosuppressive activities bind to the conserved active sites of the canonical
FKBP members such as
FKBP12, which shows
PPIase activity. These
immunophilin ligands show variable efficacy in animal models for
Parkinson's disease,
dementia, and
spinal cord injury, where the canonical
immunophilins function as chaperones and are associate with the protein folding and modulation of oxidative stress. On the other hand, in the noncanonical
FKBP members such as FKBP38, FK506-binding site is not conserved and shows neither
PPIase activity nor affinity to
FK506. Interestingly, the small molecule-mediated inhibition of the noncanonical member of
FKBP family appears to cause neuronal protection and induce proliferation of neuronal stem cells in a rat focal
cerebral ischemia model. Currently, the mechanisms of actions remain unclear. This review focuses on molecular characteristics of the canonical and noncanonical
FKBP family members and the
biological functions of their
ligands in performing neuroprotective and neurotrophic activities.