Tetratricopeptide repeat cochaperones in steroid receptor complexes

Abstract

The molecular chaperone machinery contains multiple protein components that have 1 or more structural domains composed of tetratricopeptide repeat (TPR) motifs. Many other proteins of separate or unknown function also have TPR domains, so this motif is not exclusive to molecular chaperones. A general function of TPR domains is to bind other polypeptides, but this otherwise prosaic function has been exploited in an assortment of ways that link chaperones and other protein systems into cooperative networks. Among the best-characterized TPR proteins are several cochaperones that participate in assembly and regulation of steroid receptor complexes. Steroid receptors, members of the nuclear receptor subfamily, are hormone-dependent transcription factors that regulate many vertebrate pathways of homeostasis, growth, differentiation, reproduction, and pathology and, as such, have been of great interest to biologists and clinicians. Moreover, the steroid receptors are among the first recognized native clients for chaperones and have been widely studied models for complex chaperone interactions. To provide a coherent, representative minireview of TPR protein function, the scope of this article has been narrowed down primarily to functions of steroid receptor-associated TPR cochaperones.

Fig 1.

Tetratricopeptide repeat (TPR) crystal structures. (A) The structure shown was derived from a cocrystal of the Hop TPR2a domain in complex with the MEEVD pentapeptide that terminates Hsp90 (Scheufler et al 2000). Regions of the TPR domain approximately corresponding to the 3 TPR motifs are individually colored (yellow, orange, or pink) along with the final, non-TPR alpha helix (blue). Negatively charged side chains in the MEEVD peptide (ball and stick structure) are colored red. (B) The structure shown is for squirrel monkey FKBP51 (Sinars et al 2003), which contributes to cortisol resistance in New World primates. The 2 FKBP12-like domains are indicated (FK1 and FK2), as is the Hsp90-binding TPR domain. Secondary structures are alpha helix (red cylinders), beta sheet (blue ribbons), and beta turns (green strands). Please refer to cover image for color version of this figure

Fig 2.

Pathway for assembly of steroid receptor–chaperone complexes. Assembly of steroid receptor complexes is initiated by Hsp40 and proceeds through complexes with Hsp70, Hsp90, and a variety of cochaperones. Receptor complexes containing Hsp90 and p23 have a fully competent hormone-binding domain, and hormone binding releases the receptor from the chaperone assembly cycle and promotes receptor conversion to an active transcription factor. Receptor-lacking hormone recycles through chaperone assembly, eventually being diverted to the proteasome for degradation. Tetratricopeptide repeat cochaperones (highlighted as black objects with white labels) and other components illustrated are steroid receptor monomer (R), Hsp40 (gray object marked 40), Hsp70 (70), Bag1, Chip, Hip, Hop, Hsp90 (90), p23 (23), FKBP52 (52), FKBP51 (51), CyP40 (black object marked 40), PP5, any additional immunophilin-like component (?), and steroid hormone (H)