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(Received for publication, July 12, 1996, and in revised form, November 22, 1996)
From the Cedars-Sinai Burns and Allen Research Institute, UCLA
School of Medicine, Los Angeles, California 90048, and the
Most genera of New World primates
exhibit resistance to vitamin D. These monkeys harbor high circulating
concentrations of the prohormone 25-hydroxyvitamin D and the active
vitamin D hormone 1,25-dihydroxyvitamin D. Previous work from this
laboratory indicated that resistance is associated with the
overexpression of a 60-65-kDa intracellular protein that binds vitamin
D metabolites competitively. In the current studies
25-[3H]hydroxyvitamin D3
(25-OHD3) was used as a competitive ligand to investigate
the ability of a number of small lipid molecules to interact with this
intracellular vitamin D-binding protein (IDBP) in post-nuclear extracts
of a prototypical lymphoblast cell line from the common marmoset, a
vitamin D-resistant New World primate. Only those vitamin D metabolites
with a hydroxyl moiety in the C-25 position were bound by IDBP.
Disruption of the C-25 hydroxyl obviated binding, whereas more proximal
alterations in the vitamin D side chain did not. Modifications in the
A-ring of 25-hydroxylated vitamin D metabolites, most specifically
hydroxylation of C-1, diminished but did not abolish ligand binding. Of
more than two dozen other small lipid molecules examined, only the C-19
17-hydroxysteroids, 17
Volume 272, Number 13,
Issue of March 28, 1997
pp. 8433-8440
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
AMINO ACID SEQUENCE HOMOLOGY WITH PROTEINS IN THE HSP-70
FAMILY
and
Beckman Research Institute, City of Hope Hospital and
Medical Center, Los Angeles, California 92714
-estradiol and testosterone, and the C-21
steroid progesterone were found to be capable of binding specifically
to IDBP. Using a combination of physical and serial chromatographic
techniques, we enriched IDBP 25-OHD3 binding activity 17,588-fold in extracts of B95-8 cells. Two-dimensional sodium dodecyl
sulfate-polyacrylamide gel electrophoresis of this purified fraction
demonstrated a predominant 65-kDa molecular species with a pI ~ 4.5. Seven different peptide fragments were isolated from the 65-kDa
protein, each possessing sequence similarity to the hsp-70 family of
proteins. Ligand binding analyses confirmed that human inducibly
expressed hsp-70-bound 25-OHD3 with approximately similar
affinity (~10
7 M) as did purified IDBP. In
summary, these results suggest a novel action for the hsp-70 family of
proteins as intracellular vitamin D- and gonadal steroid
hormone-binding molecules.
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