Calcineurin (CN) is a unique serine/threonine protein phosphatase
(PP3 or PP2B) in its regulation by the second messenger
Ca2+ and calmodulin. It is involved in many biological processes,
including immune responses, the second messenger cAMP
pathway, Na/K ion transportation in nephron, cell cycle regression
in lower eukaryotes, cardiac hypertrophy, and memory
formation. Calcineurin has been shown to be a common receptor for two
immunophilin-immunosuppressant complexes,
cyclophilin A-cyclosporin A (CyPA-CsA) and FKBP-FK506. The binding
of CyPA-CsA or FKBP-FK506 inhibits the
calcium-dependent dephosphorylation of the nuclear factor of activated
T cell (NFAT) by CN, thus blocking T cell
receptor-mediated cytokine transcription and T-cell activation. It
has been a mystery how two structurally distinct
immunophilin-immunosuppressant complexes recognize a common target.
Our crystal structure of CN-CyPA-CsA reveals that CyPA-CsA binds to
a composite surface as does FKBP-FK506. While
majority of the CN residues involved in the binding are common for
both immunophilin-immunosuppresant complexes, a
significant number of the residues are distinct. Besides, the
patterns of recognition are dramatically different for FKBP-FK506
and CyPA-CsA. The simultaneous interaction of CyPA with both
composite surface and active site of calcineurin suggests that
the composite surface may serve as a substrate recognition site responsible
for the narrow substrate specificity of calcineurin.
Surface presentation of calcineurin in complex with cyclophilin A (worm)
and cyclosporin A (balls).
Superposition of CN-CyPA-CsA over CN-FKBP-FK506. The color ribbons
are: golden for CnA, cyan for CnB, red for
CyPA, green for FKBP. Pink balls represent two divalent metals. Pink
sticks are CsA. Blue sticks are FK506. The recognition
surface for the binding of immunophlins-immunosuppresants is highlighted
by green dots.