Insights into Immunophilin Structure and Function

Abstract

The immunophilins are proteins which are capable of influencing the immune response in combination with an immunosuppressive drug. Their natural function, however, is mainly the cis/trans isomerization of peptidyl-prolyl bonds in other proteins. This review lists all immunophilin structure coordinates currently available in the RCSB protein data bank and highlights the key active-site factors that define their catalytic and immunological action. In addition, an overview of biologically-relevant functions is provided for various immunophilin members.

Plant immunophilins: a review of their structure-function relationship

“…Sequence alignment of the FKBDs of AtFKBP13, AtFKBP43 and the three FKBDs of TaFKBP73, along with the FKBD of hFKBP12 (Fig. 1) reveals that of the 11 key active-site residues inside the hydrophobic pocket that are involved in PPIase function (Y27, F37, D38, F47, F49, V56, I57, W60, Y83, I92 and F100; hFKBP12 numbering) [89], all 11 are conserved in the first FKBD of TaFKBP73 and 10 are conserved in AtFKBP13. In TaFKBD73-3 only six out of the 11 active site residues are conserved and only 2 are conserved in TaFKBD73-2.…”

“…The structures of mammalian cyclophilins, such as CYPA-H and CYPJ are known from human, Mus musclus, Bos taurus, Equus caballus and Macaca mulatta [89,120,121]. The crystal structures of apo-form, mutants and complexes with immunosuppressant drugs and peptide substrates are available for cyclophilins from Acanthamoeba polyphaga mimivirus, Thermotoga, Escherichia,-Mycobacterium, Azotobacter, Aspergillus, Piriformospora, Moniliophthora, Saccharomyces, Cryptosporidium, Encephalitozoon, Leishmania, Malassezia, Plasmodium, Trypanasoma, Toxoplasma, Brugia, Schistostoma and Caenorhabditis [89,122,123].…”

Regulatory factors for the assembly of thylakoid membrane protein complexes

“…The immunophilin family includes FKBP (FK-506 binding protein) and cyclophilin proteins originally identified as receptors for immunosuppressive drugs (FK506 and cyclosporin A) [71,72]. Most immunophilin proteins have PPIase (peptidyl -prolyl cis -trans isomerase) activity that catalyses the cis-trans conversion of X-Pro peptide bonds, a rate-limiting step in protein folding [71,72]. This association with protein-folding capability suggests that these enzymes play a central role in the biogenesis of protein complexes, probably including PSII complexes.…”

Interaction of p53 with prolyl isomerases: Healthy and unhealthy relationships

“…Some FKBPs contain multiple PPIase domains and a tetratricopeptide (TPR) domain that mediates interaction with Hsp90 [20]. Despite having a PPIase domain, a large fraction of FKBPs is catalytically inactive, implying that their functions do not necessarily involve enzymatic activity [30].…”

“…Indeed, any situation that interferes with correct folding may result in protein misfolding, toxic accumulation, potential aggregation and consequently loss of function or even cell toxicity. As a consequence, deregulation of different PPIases such as Pin1, CypA, CypB, Cyp40, FKBP-12, FKBP-51, and FKBP-52 has been found associated with pathological conditions such as cancer and neurodegeneration as well as with viral infection [20,30,50].…”