Human Hsp90 cochaperones: perspectives on tissue-specific expression and identification of cochaperones with similar in vivo functions

Abstract

The Hsp90 molecular chaperone is required for the function of hundreds of different cellular proteins. Hsp90 and a cohort of interacting proteins called cochaperones interact with clients in an ATP-dependent cycle. Cochaperone functions include targeting clients to Hsp90, regulating Hsp90 ATPase activity, and/or promoting Hsp90 conformational changes as it progresses through the cycle. Over the last 20 years, the list of cochaperones identified in human cells has grown from the initial six identified in complex with steroid hormone receptors and protein kinases to about fifty different cochaperones found in Hsp90-client complexes. These cochaperones may be placed into three groups based on shared Hsp90 interaction domains. Available evidence indicates that cochaperones vary in client specificity, abundance, and tissue distribution. Many of the cochaperones have critical roles in regulation of cancer and neurodegeneration. A more limited set of cochaperones have cellular functions that may be limited to tissues such as muscle and testis. It is likely that a small set of cochaperones are part of the core Hsp90 machinery required for the folding of a wide range of clients. The presence of more selective cochaperones may allow greater control of Hsp90 activities across different tissues or during development.

Keywords: Aha1; Cdc37; Cochaperone; Hsp90; Molecular chaperone; Tetratricopeptide repeat.

Fig. 1

a Simplified model of the Hsp90 folding pathway. The client protein (yellow, Cl.) bound to Hsp70 (light blue) is targeted to the open conformation of Hsp90 (dark gray) in a process facilitated by Hop (dark blue). Nucleotide binding promotes dimerization of the amino-termini of Hsp90 and displacement of Hop by Aha1 (red, A) and Cyp40 (green, 40). The closed conformation is further stabilized by p23 (orange, 23). b Additional cochaperones that share a CS domain with p23, or a TPR domain with Hop or Cyp40 have also been found in Hsp90 complexes. Other cochaperones do not contain either of those domains

Fig. 2

a Phylogenetic tree showing homology of cochaperones with p23-like CS domains. The sequences corresponding to the CS domain of human cochaperones were aligned with Clustal Omega. The accession sequences for each cochaperone are listed in Table S1. b The Genotype-Tissue Expression (GTEx) database (gtexportal.org) was used to compare mRNA expression data for each of the cochaperones across a range of human tissues. Brain = frontal cortex, heart = atrial appendage. The hatched polygons show the mean transcripts per million (TPM) of the mRNA encoding the indicated cochaperone in the tissue shown. Darker colors represent higher expression levels

Fig. 3

a Phylogenetic tree showing homology of cochaperones containing TPR domains. The sequences corresponding to the TPR domains of human cochaperones were aligned with Clustal Omega. The accession sequences for each cochaperone are listed in Table S2. b, c The Genotype-Tissue Expression (GTEx) database (gtexportal.org) was used to compare mRNA expression data for each of the cochaperones across a range of human tissues. Brain = frontal cortex, heart = atrial appendage. The hatched polygons show the mean transcripts per million (TPM) of the mRNA encoding the indicated cochaperone in the tissue shown. Darker colors represent higher expression levels