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J Biol Chem, Vol. 273, Issue 36, 23509-23516, September 4, 1998
Structure-Function Analysis of the Human Insulin-like Growth
Factor Binding Protein-4
Xuezhong
Qin §,
Donna D.
Strong §¶ ,
David J.
Baylink §¶, and
Subburaman
Mohan §¶**
From the Department of Mineral Metabolism, J. L. Pettis Memorial Veterans Medical Center and Departments of
§ Medicine, ¶ Biochemistry, ** Physiology, and
Microbiology and Molecular Genetics, Loma Linda University,
Loma Linda, California 92357
To identify the molecular mechanism by which
insulin-like growth factor binding protein-4 (IGFBP-4) exerts its
inhibitory effects on insulin-like growth factor (IGF) actions, we
localized and determined the role of the IGF binding domain in
modulating IGF actions in human osteoblasts. Deletion analysis using
IGFBP-4 expressed in bacteria revealed that the N-terminal sequence
Leu72-Ser91 was essential for IGF
binding. The C-terminal fragments
(His121-Glu237 or
Arg142-Glu237) did not bind to IGF but loss of
these regions decreased IGF binding activity. Detailed deletion
analysis identified the residues Cys205-Val214
as the motif to facilitate IGF binding. Mitogenic studies revealed that
an IGFBP-4 mutant (His74 replaced by Pro74) and
an N-terminal peptide (N terminus to Thr71) with little IGF
binding activity failed to inhibit IGF-II-induced human osteoblast
proliferation. An N-terminal peptide (N terminus to Asn182)
with reduced IGF binding activity inhibited IGF action but with lower
potency. In contrast, an IGFBP-4 mutant (His74 replaced
with Ala74) exhibited similar IGF binding activity and
potency in inhibiting the activity of IGF-II compared with the wild
type. Therefore, the N-terminal sequence
(Leu72-Ser91) and the C-terminal sequence
(Cys205-Val214) are necessary to form the high
affinity IGF binding domain, which is the major structural determinant
of the IGFBP-4 function.
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.

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Copyright © 1998 by the American Society for Biochemistry and Molecular Biology.
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