Functional comparison of human and Drosophila Hop reveals novel role in steroid receptor maturation.
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.
Carrigan
Patricia E
PE
Department of Biochemistry and Molecular Biology, Mayo Clinic Scottsdale, Scottsdale, Arizona 85259, USA.
Riggs
Daniel L
DL
Chinkers
Michael
M
Smith
David F
DF
D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D003001:Cloning, Molecular; D004330:Drosophila / Q000502:physiology*; D029721:Drosophila Proteins; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000737:chemistry* / Q000502:physiology; D020962:Heterotrimeric GTP-Binding Proteins; D006801:Humans; D053612:Janus Kinases; D051379:Mice; D008969:Molecular Sequence Data; D011505:Protein-Tyrosine Kinases / Q000737:chemistry* / Q000502:physiology; D011965:Receptors, Glucocorticoid / Q000502:physiology*; D011987:Receptors, Steroid / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors
D033942:Adaptor Proteins, Vesicular Transport; D029721:Drosophila Proteins; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D011965:Receptors, Glucocorticoid; D011987:Receptors, Steroid; D011993:Recombinant Fusion Proteins; C079373:STIP1 protein, human; C475144:TTC1 protein, human; D014157:Transcription Factors; D011505:Protein-Tyrosine Kinases; D053612:Janus Kinases; C085845:hop protein, Drosophila; D020962:Heterotrimeric GTP-Binding Proteins