Proline isomerases at the crossroads of protein folding, signal transduction, and immunosuppression

Heitman, J. and Movva, N. R. and Hall, M. N.. (1992) Proline isomerases at the crossroads of protein folding, signal transduction, and immunosuppression. The New Biologist, Vol. 4, no. 5. pp. 448-460.

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Official URL: http://edoc.unibas.ch/dok/A5258198

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The immunosuppressants cyclosporin A (CsA), FK506, and rapamycin block T-cell activation by interfering with signal transduction. The institution of CsA therapy for prophylaxis against graft rejection revolutionized human organ transplants, and clinical trials with FK506 and rapamycin are in progress. The targets for these drugs, cyclophilin for CsA and FKBP for FK506 and rapamycin, are members of two unrelated families of ubiquitous, highly conserved, abundant proteins. Although unrelated, both cyclophilin and FKBP catalyze proline isomerization and may fold proteins. The structures of both cyclophilin and FKBP have been determined, in some cases in complex with drugs or substrates. The cyclophilin-CsA and FKBP-FK506 complexes prevent T-cell response to antigen, bind and modulate the activity of the protein phosphatase calcineurin, and prevent nuclear import of a subunit of NF-AT, a T-cell activation transcription factor. In contrast, rapamycin blocks T-cell responses to IL-2. Yeast genetic studies suggest that the FKBP-rapamycin target is a protein complex involved in cell cycle progression. Further studies should provide fundamental insights into T-cell activation, signal transduction, and protein folding, and hold the promise of more specific immunosuppressive therapies.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Growth & Development > Biochemistry (Hall)
UniBasel Contributors:Hall, Michael N.
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:W. B. Saunders
Note:Publication type according to Uni Basel Research Database: Journal article
Last Modified:22 Mar 2012 14:22
Deposited On:22 Mar 2012 13:30

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