Human pancreas-specific protein disulfide isomerase homolog (PDIp) is an intracellular estrogen-binding protein that modulates estrogen levels and actions in target cells.
Earlier studies showed that protein disulfide isomerase (PDI), a well-known protein folding catalyst, can bind estrogens. Whether other PDI homologs can also bind estrogens, and if so, what are the biological functions of this unique property are not known at present and thus are the subjects of our present investigation. Here we report that, of the six representative PDI homologs examined (human PDI, PDIp, ERp57, ERp72, PDIA6 and rat PDIr), only the human pancreas-specific PDI homolog (PDIp) had a similar binding affinity for radiolabeled 17beta-estradiol (E(2)) as did PDI, with apparent K(d) values of 1.5+/-0.3 and 1.5+/-0.2microM, respectively. However, PDIp and PDI had distinctly different binding preference for several estrogen analogs. Moreover, we found that PDIp could serve as a high-capacity intracellular E(2)-binding protein and could modulate the intracellular concentrations of E(2) in cultured mammalian cells as well as in human pancreatic tissue. The PDIp-bound E(2) in a cell could be released following a drop in the extracellular E(2) concentrations, and the released E(2) could then augment estrogen receptor-mediated transcriptional activity. Notably, the estrogen receptor alpha and beta were also found to be expressed in rodent and human pancreatic tissues where high levels of PDIp were detected. Altogether, these data show that, in addition to its well-documented function as a protein folding catalyst, PDIp can also serve as an effective modulator of the cellular levels and biological actions of endogenous estrogens in certain target sites (such as the pancreas) where estrogen receptors and PDIp are co-present.
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, 66160, USA.
Xin-Miao
XM
Fu
Bao Ting
BT
Zhu
D000818:Animals; D002478:Cells, Cultured; D004958:Estradiol / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000032:analysis*; D047629:Estrogen Receptor beta / Q000032:analysis*; D006801:Humans; D010179:Pancreas / Q000166:cytology / Q000201:enzymology*; D011485:Protein Binding; D019704:Protein Disulfide-Isomerases / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D011960:Receptors, Estrogen / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D014158:Transcription, Genetic
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D011960:Receptors, Estrogen; D004958:Estradiol; D019704:Protein Disulfide-Isomerases