Abstract
In this technical note, we describe analyses of more than 15,000 sequences of FK506-binding proteins (FKBP) and cyclophilins, also known as peptidyl-prolyl cis/trans isomerases (PPIases). We have developed a novel way of displaying relative changes of amino acid (AA)-residues at a given sequence position by using heat-maps. This type of representation allows simultaneous estimation of conservation level in a given sequence position in the entire group of functionally-related paralogues (multigene family of proteins). We have also proposed that at least two FKBPs, namely FKBP36, encoded by the Fkbp6 gene and FKBP51, encoded by the Fkbp5 gene, can form dimers bound via a disulfide bridge in the nucleus. This type of dimer may have some crucial function in the regulation of some nuclear complexes at different stages of the cell cycle.
Highlights
About 30 years ago, an exciting adventure began in finding some correlations between pharmacological activities of macrocyclic hydrophobic drugs, namely the cyclic peptide cyclosporineA (CsA), and two macrolides, namely FK506 and rapamycin, which have profound and clinically useful immunosuppressive effects, especially in organ transplantations and in combating some immune disorders
It has been found that these molecules bind to abundant cytosolic proteins, which have significant potential to accelerate cis/trans isomerization of X-Pro bonds in synthetic peptides and proteins and which are called since peptidylprolyl cis/trans isomerases (PPIases) [1,2,3]
For around 25 years, it has been believed that the immunosuppressive activity of the CyPA/CsA and FKBP12a/FK506 complexes are due to blocking the access to the activity site of calcineurin-A/calcineurin-B/calmodulin complex [4], which in turn causes retention of the phosphorylated form of the transcription factor that is a key factor of transcription of some cytokines
Summary
About 30 years ago, an exciting adventure began in finding some correlations between pharmacological activities of macrocyclic hydrophobic drugs, namely the cyclic peptide cyclosporineA (CsA), and two macrolides, namely FK506 and rapamycin, which have profound and clinically useful immunosuppressive effects, especially in organ transplantations and in combating some immune disorders. Research on the immunosuppressive activities of these three molecules has, been rapidly advancing and has led to an ingenious proposition that there must be additional intracellular factors whose blocking of their enzymatic activity is the principal cause of immunosuppression. This reasoning was based on the fact that the intracellular concentration of cyclophilin-A and FKBP-12a are too high for being totally saturated by the immunosuppressive molecules under physiological conditions. For around 25 years, it has been believed that the immunosuppressive activity of the CyPA/CsA and FKBP12a/FK506 complexes are due to blocking the access to the activity site of calcineurin-A/calcineurin-B/calmodulin complex [4], which in turn causes retention of the phosphorylated form of the transcription factor (nuclear factor of activated T cells, NF-AT) that is a key factor of transcription of some cytokines
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