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FKBP immunophilins and Alzheimers disease: A chaperoned affair
WEIHUAN CAO and MARY KONSOLAKI*
Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA
*Corresponding author (Fax, +01-732-445-6920; Email, [email protected])
The FK506-binding protein (FKBP) family of immunophilins consists of proteins with a variety of proteinprotein interaction domains and versatile cellular functions. Analysis of the functions of immunophilins has been the focus of studies in recent years and has led to the identification of various molecular pathways in which FKBPs play an active role. All FKBPs contain a domain with prolyl cis/trans isomerase (PPIase) activity. Binding of the immunosuppressant molecule FK506 to this domain inhibits their PPIase activity while mediating immune suppression through inhibition of calcineurin. The larger members, FKBP51 and FKBP52, interact with Hsp90 and exhibit chaperone activity that is shown to regulate steroid hormone signalling. From these studies it is clear that FKBP proteins are expressed ubiquitously but show relatively high levels of expression in the nervous system. Consistent with this expression, FKBPs have been implicated with both neuroprotection and neurodegeneration. This review will focus on recent studies involving FKBP immunophilins in Alzheimers-disease-related pathways.
[Cao W and Konsolaki M 2011 FKBP immunophilins and Alzheimers disease: A chaperoned affair. J. Biosci. 36 493498] DOI 10.1007/s12038-011-9080-7
1. Overview of immunophilins
In general, immunophilins are proteins with a cytoplasmic localization and their physiological function is that of a chaperone with peptidyl-prolyl cis/trans isomerase (PPIase) activity (Barik 2006). Interestingly, the name immunophilin reflects the discovery of these proteins as binding partners of exogenous ligands with immunosuppressant properties, such as cyclosporine A, rapamycin and FK506. Both cyclosporine A, produced by the fungus Beauveria nivea, and rapamycin and FK506, produced by the bacteria Streptomyces hygroscopicus and S. tsukubaensis, respectively, are normally never encountered by mammalian cells. However, binding of these ligands to mammalian immunophilins has been shown to induce immunosuppression (Dawson et al. 1994), leading to a fantastic success for the transplantation field. Subsequent to the discovery of their immunosuppressive function, immunophilins were shown to be involved in various cellular signalling pathways, including calcium homeostasis, steroid receptor signalling and,
recently, copper trafficking (reviewed in Avramut and Achim 2003; Sanokawa-Akakura et al. 2004).
The immunophilin family comprises the cyclophilins, which bind cyclosporine, FK506-binding proteins (FKBPs), which bind...