Functional Comparison of Human and Drosophila Hop Reveals Novel Role in Steroid Receptor Maturation

Expert Analysis

Hsp70 / Hsp90 organizing protein (Hop) coordinates Hsp70 and Hsp90 interactions during assembly of steroid receptor complexes. Hop is composed of three tetratricopeptide repeat (TPR) domains (TPR1, TPR2a, and TPR2b) and two DP repeat domains (DP1 and DP2); Hsp70 interacts directly with TPR1 and Hsp90 with TPR2a, but the function of other domains is less clear. Human Hop and the Saccharomyces cerevisiae ortholog Sti1p, which share a common domain arrangement, are functionally interchangeable in a yeast growth assay and in supporting the efficient maturation of glucocorticoid receptor (GR) function. To gain a better understanding of Hop structure/function relationships, we have extended comparisons to the Hop ortholog from Drosophila melanogaster (dHop), which lacks DP1. Although dHop binds Hsp70 and Hsp90 and can rescue the growth defect in yeast lacking Sti1p, dHop failed to support GR function in yeast, which suggests a novel role for Hop in GR maturation that goes beyond Hsp binding. Chimeric Hop constructs combining human and Drosophila domains demonstrate that the C-terminal domain DP2 is critical for this previously unrecognized role in steroid receptor function.

Functional maturation of steroid receptors requires multi-step assembly with molecular chaperones, and Hop, which binds both Hsp70 and Hsp90, can facilitate the progression through the intermediate stages of assembly. The early steps in assembling receptor/chaperone complexes are the binding of Hsp40 to a receptor monomer followed by recruitment of Hsp70. Hop-Hsp90 complexes are then recruited to bind the receptor-associated Hsp70. In a transition that remains poorly understood, Hsp90 becomes directly associated with the receptor, and Hsp70 and Hop leave the complex. The Hsp90 co-chaperone p23 binds to Hsp90, stabilizing its association with the receptor, and immunophilin-related co-chaperones bind Hsp90 at a site vacated by Hop. Only when the receptor has achieved assembly with Hsp90 and p23 does it attain full hormone binding ability.

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