A Conserved Docking Surface on Calcineurin Mediates Interaction with Substrates and Immunosuppressants
Por:
A. RODRIGUEZ, J. ROY, S. MARTINEZ-MARTINEZ, M. LOPEZ-MADERUELO, P. NINO-MORENO, L. ORTI, D. PANTOJA-UCEDA, A. PINEDA-LUCENA, M. CYERT and J. REDONDO
Publicada:
13 mar 2009
Resumen:
The phosphatase calcineurin, a target of the immunosuppressants cyclosporin A and FK506, dephosphorylates NFAT transcription factors to promote immune activation and development of the vascular and nervous systems. NFAT interacts with calcineurin through distinct binding motifs: the PxIxIT and LxVP sites. Although many calcineurin substrates contain PxIxIT motifs, the generality of LxVP-mediated interactions is unclear. We define critical residues in the LxVP motif, and we demonstrate its binding to a hydrophobic pocket at the interface of the two calcineurin subunits. Mutations in this region disrupt binding of mammalian calcineurin to NFATC1 and the interaction of yeast calcineurin with substrates including Rcn1, which contains an LxVP motif. These mutations also interfere with calcineurin-immunosuppressant binding, and an LxVP-based peptide competes with immunosuppressant-immunophilin complexes for binding to calcineurin. These studies suggest that LxVP-type sites are a common feature of calcineurin substrates, and that immunosuppressant-immunophilin complexes inhibit calcineurin by interfering with this mode of substrate recognition.
Filiaciones:
A. RODRIGUEZ:
CNIC, Dept Vasc Biol & Inflammat, Madrid 28029, Spain
Univ Autonoma Madrid, Fac Ciencias, Dept Biol Mol, E-28049 Madrid, Spain
J. ROY:
Stanford Univ, Dept Biol, Stanford, CA 94305 USA
S. MARTINEZ-MARTINEZ:
CNIC, Dept Vasc Biol & Inflammat, Madrid 28029, Spain
M. LOPEZ-MADERUELO:
CNIC, Dept Vasc Biol & Inflammat, Madrid 28029, Spain
P. NINO-MORENO:
CNIC, Dept Vasc Biol & Inflammat, Madrid 28029, Spain
:
Ctr Invest Principe Felipe, Dept Biol Estruct, Valencia 46012, Spain
D. PANTOJA-UCEDA:
Ctr Invest Principe Felipe, Dept Biol Estruct, Valencia 46012, Spain
:
Ctr Invest Principe Felipe, Dept Biol Estruct, Valencia 46012, Spain
M. CYERT:
Stanford Univ, Dept Biol, Stanford, CA 94305 USA
J. REDONDO:
CNIC, Dept Vasc Biol & Inflammat, Madrid 28029, Spain
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