It Takes Two Binding Sites for Calcineurin and NFAT to Tango

Department of Pharmacology, Johns Hopkins School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.
Molecular cell (Impact Factor: 14.02). 04/2009; 33(6):676-8. DOI: 10.1016/j.molcel.2009.03.005
Source: PubMed

ABSTRACT In a recent issue of Molecular Cell, Rodríguez et al. (2009) identified the NFAT LxVP motif binding site as the same composite surface formed by the two calcineurin subunits that is recognized by the cyclophilin-CsA and FKBP-FK506 complexes.

20 Reads
  • [Show abstract] [Hide abstract]
    ABSTRACT: In the past few years, many researches have provided us with much data demonstrating the abilities of synthetic peptides to impact immune response in vitro and in vivo. These peptides were designed according to the structure of some important protein molecules which play a key role in immune response, so they act with specific targets. The class I and II MHC-derived peptides inhibit the TCR recognition of antigen peptide-MHC complex. Rationally designed CD80 and CD154-binding peptides block the interaction between cell surface costimulatory molecules on antigen-presenting cells (APCs) and T cells. Some peptides were designed to inhibit the activities of cell signal proteins, including JNK, NF-κB and NFAT. Some peptide antagonists competitively bind to important cytokines and inhibit their activities, such as TNF-α, TGF-β and IL-1β inhibitory peptides. Adhesion molecule ICAM-1 derived peptides block the T cell adhesion and activation. These immunoregulatory peptides showed therapeutic effect in several animal models, including collagen-induced arthritis (CIA), autoimmune cystitis model, murine skin transplant model and cardiac allograft model. These results give us important implications for the development of a novel therapy for immune mediated diseases.
    Peptides 10/2010; 32(2):408-14. DOI:10.1016/j.peptides.2010.10.019 · 2.62 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Calcineurin (protein phosphatase 3, Cn) is best known for its central position in Ca(2+)-dependent T-cell signaling. Interest in calcineurin has, however, conserved its momentum as new Ca(2+)-dependent pathways have been steadily surfacing in several other cell types, such as brain, heart, skin cells and beta pancreatic cells, and Cn appears to serve as a central controller of stress, immune response, and cellular proliferation and differentiation. Calcineurin is the principal target of the immunosuppressive drugs cyclosporin A (CsA) and tacrolimus (TRL). Therapy based on these immunosuppressants has markedly reduced the incidence of transplant rejection in allograft recipients. In addition, these drugs have proven very useful for patients suffering from chronic inflammatory skin conditions. Unfortunately, their application is somewhat limited by a broad spectrum of toxic side-effects, affecting several organ systems. This calls for enhancements in the design of this class of immunosuppressants. An intricate constellation of regulatory systems allows for precise modulation and adaptation of calcineurin activity in vivo. The last few years have been very fruitful in elucidating several long-standing issues regarding the binding patterns of substrates and inhibitors to Cn. This new knowledge may enable more precise manipulation of the Ca(2+)-calcineurin pathway in the near future, preferably targeted towards one specific substrate or cell system. In this review, we will discuss the factors and mechanisms underlying calcineurin activity regulation and their exploitation in recent approaches towards better immunosuppressants.
    Current Medicinal Chemistry 01/2011; 18(2):301-15. DOI:10.2174/092986711794088407 · 3.85 Impact Factor
  • Journal of Clinical Densitometry 04/2011; 14(2):154-154. DOI:10.1016/j.jocd.2011.02.010 · 2.03 Impact Factor
Show more