FK506 Binding Protein

FK506 Binding Protein

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About FK506 Binding Protein \ FKBP:

FK506 Binding Protein is related to the cyclophilins in terms of function, although they do not share the same amino acid sequence. Sometimes referred to as FKBP, FK506 binding protein is a member of the immunophilin family and has been shown to exist in various eukaryotes.

FK506 Binding Protein Mechanisms
FKBP refers to a number of different binding proteins, which may have different mechanisms of action. However, the FK506 binding protein has been shown to act as molecular switches by binding directly to their target proteins and altering their shape and structure. For example, the FKBP12-FK506 complex is created when FK506 binds to cytosolic FKBP12.

FKBP Function
FK506 binding proteins have a number of functions, some of which are still emerging. Within the FK506 binding proteins family, FKBP12 is known to bind with immunosuppressant drugs, Rapamycin, and Tacrolimus (also known as FK506). Operating as a cis/trans peptidyl prolyl isomerase (PPIase), FKBP12 then begins the process of interconversion between prolyl cis/trans conformations.With a range of functions, FKBPs are involved in protein folding, apoptosis, cellular functioning, and transcription. Due to their varied functions, studies have suggested that FKBPs may be involved with the regulation of cardiac function, immunosuppression, neurodegenerative diseases, cancer, neuronal development, and function, as well as heart disease.

FK506 Binding Protein Structure
With the FK506 binding proteins family, FKBP12 is expressed in all types of tissues and has been identified as a 12 kDa cytosolic protein. FKBP38 contains 413 amino acids and has a predicted size of 45 kDa, however, there have been some discrepancies over the exact structure of FKBP38 in the past. Residing in both the nucleus and cytoplasm, FKBP52 is a co-chaperone of heat-shock protein 90 (Hsp90) and has an active role in steroid receptor regulation. Sharing 60% of sequencing homology with FKBP52, FKBP51 also features Ca2+/CaM binding motif, three TPR domains and two PPIase domains.
In contrast, FKBP36 lacks PPIase activity but contains a C-terminal TPR domain and an N-terminal PPIase domain. Whilst FKBP36 lacks PPIase activity, it remains able to bind with various proteins due to its TPR and PPIase domains. FKBP57 also contains a TPR domain at its C-terminus, as well as a PPIase domain at its N-terminus. Defined as an aryl hydrocarbon receptor-interacting protein, FKBP57 doesn’t exhibit PPIase activity, nor does it bind to FK506. However, its structure does enable it to interact with Hsp90 via its TPR and PPIase domains.
In addition to this, FKBPP25 features a nuclear targeting sequence and includes a PPIase domain at its C-terminus and a hydrophilic helix-loop-helix (HLH) motif at its N-terminus. Finally, FKBP133, sometimes known as WAFL, is comprised of a PPIase domain and a Wiskott-Aldrich syndrome protein homology region1(WH1).

FKBP Interactions
TPR domains are commonly involved in mediating protein-protein interactions, which means many of the proteins within the FK506 family work in this way. In relation to immunosuppression, the FK506-FKBP12 complex interacts with calcineurin (CaN), which is a Ca2+-dependent serine-threonine phosphatase. When present in muscle cells, FKBP12 has been shown to interact with the Ca2+ release channels of the sarcoplasmic reticulum (SR) ryanodine receptors (RyRs), whilst FKBP57 interacts with hsp90 via both PPIase and TPR domains.