FKBP family proteins : immunophilins with versatile biological functions

Abstract

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.