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Proteins in the Heat Shock-70 Family Specifically Bind 25-Hydroxyvitamin D₃ and 17ß-Estradiol¹

Burns and Allen Research Institute and Division of Endocrinology and Metabolism, Cedars-Sinai Medical Center, University of California School of Medicine, Los Angeles, California 90048

Address all correspondence and requests for reprints to: John S. Adams, M.D., University of California School of Medicine, Division of Endocrinology and Metabolism, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Room B 131, Los Angeles, California 90048.

Abstract

Most New World primates evolved to express a form of compensated resistance to steroid hormones from the gonads and adrenal glands as well as to the hydroxylated vitamin D₃ prohormone, 25-hydroxyvitamin D₃ (25OHD₃), and the vitamin D hormone 1,25-dihydroxyvitamin D₃ [1,25-(OH)₂D₃] originating from the liver and kidney, respectively. We recently demonstrated that this form of resistance is associated with the overexpression of a novel member of the 70-kDa heat shock protein (hsp-70) molecular chaperone family, which we have termed the intracellular vitamin D binding protein (IDBP). In the current report we more closely examine the ligand-binding capability of purified IDBP and two other mammalian hsp-70 family members, heat-inducible (hsp-70) and constitutively expressed (hsc-70) hsp-70 proteins. Purified IDBP, hsp-70, and hsc-70 all bound 25OHD₃ with relatively high affinity; the mean K_d for 25OHD₃ ranged from 0.5–2.2 nmol/L (rank order: IDBP hsp-70 hsc-70). By Scatchard analysis, high affinity, specific binding of 1,25-(OH)₂D₃ was not reproducibly observed for any of the three members of the hsp-70 family. Unlike purified IDBP, hsc-70 and hsp-70 were also competent binders of the gonadal steroid 17ß-estradiol (mean K_d for 25OHD₃, 2.5 and 6.6 nmol/L by hsc-70 and hsp-70, respectively), but not of two other gonadal hormones, progesterone and testosterone. These data suggest that IDBP is relatively specific for 25OHD₃ and that additional hsp-70-like binding proteins are present in unpurified New World primate cell extracts that are specific for 1-hydroxylated vitamin D metabolites as well as other gonadal steroid hormones.

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