Functions of the Hsp90-Binding FKBP Immunophilins - The Networking of Chaperones by Co-chaperones - page 35

Introduction
Immunophilins are a large, functionally diverse group of proteins that are defined
by their ability to bind immunosuppressive ligands. The immunophilins minimally
contain a peptidyl-prolyl cis-trans isomerase (PPIase; also termed rotamase) do-
main to which the immunosuppressive drugs bind. Early investigations into the
PPIase enzymatic activity led to the belief that the immunosuppressive drugs
elicited their effects by inhibiting the PPIase activity. However, some compounds
binding the PPIase active site efficiently inhibit PPIase activity without inducing
immunosuppression, so PPIase activity is not critical for immune responses. It is
now known that effector domains on the immunosuppressive drugs project from
the PPIase pocket. This allows the immunophilin-drug complex to bind tightly
to and inhibit calcineurin or target of rapamycin, signal transduction proteins re-
quired for immune responses (see Hamilton and Steiner 1998 for a detailed review
on the mechanisms by which immunophilins and their ligands suppress immune
responses).
Since the initial identification of the immunophilin proteins, multiple family
members have been identified in all major branches of life. Some immunophilins
are small proteins containing only a single PPIase domain while others are large
multidomain proteins that contain one or more PPIase domains, as well as addi-
tional functional domains. The immunophilins are divided into two groups based
on their ability to bind different immunosuppressive ligands: the FK506 binding
proteins (FKBP), which also bind rapamycin, and the cyclosporin-A binding pro-
teins or cyclophilins (CyP). The PPIase domains of FKBP and cyclophilins are
structurally distinct and likely evolved independently. On the other hand, some
members of either the FKBP or cyclophilin families contain a structurally similar
tetratricopeptide repeat (TPR) domain that targets binding to heat shock protein
90 (Hsp90).
Hsp90 is an abundant molecular chaperone that interacts with a broad array of
protein clients that regulate numerous important cellular pathways. Among the
known Hsp90 clients are transcription factors (e.g., steroid hormone receptors, heat
shock transcription factor 1, aryl hydrocarbon receptor), both serine/threonine and
tyrosine kinases (e.g., Raf and Src-related kinases), and key regulatory enzymes
(e.g., nitric oxide synthase and telomerase). A compilation of known Hsp90 clients
maintained by Didier Picard at Univ. of Geneva can be accessed at: http://www.
picard.ch/downloads/Hsp90interactors.pdf.
In concert with other chaperone proteins, Hsp90 facilitates client folding and
proteolytic stability but can also promote client degradation. In the case of steroid
receptors, Hsp90 and its associated co-chaperones also regulate receptor activity.
Hsp90 binding to steroid receptors must be preceded by transient receptor interac-
tions with Hsp40, Hsp70, and associated co-chaperones. Hsp90, which is recruited
as a dimer in the latter stages of complex assembly, binds directly to the receptor
ligand binding domain and stabilizes a receptor conformation that is competent for
hormone binding. Proteins that are associated with Hsp90 in the functionally mature