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Volume 271, Number 24,
Issue of June 14, 1996
pp. 13948-13952
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
Biosensor Measurement of the Binding of Insulin-like Growth
Factors I and II and Their Analogues to the Insulin-like Growth
Factor-binding Protein-3
(Received for publication, February 15, 1996)
Anders
Heding
,
Raj
Gill
§
,
Yasushi
Ogawa
¶
,
Pierre
De
Meyts
and
Ronald M.
Shymko
From the Hagedorn Research Institute, Niels Steensens
Vej 6, DK-2820 Gentofte, Denmark, the § Department of
Crystallography, Birkbeck College, Malet Street, London WC1E 7HX,
United Kingdom, and ¶ Celtrix Pharmaceuticals, Inc.,
Santa Clara, California 95052
Most insulin-like growth factor (IGF) molecules
in the circulation are found in a 150-kDa complex containing
IGF-binding protein-3 (IGFBP-3) and an acid-labile subunit, which does
not itself bind IGF. Affinities (Kd values) between
0.03 and 0.5 nM have been reported for IGF-I/IGFBP-3
binding, but no kinetic data are available. In this study we measured
the high affinity binding of unlabeled IGFs and IGF analogues to
recombinant unglycosylated IGFBP-3, using a BIAcoreTM instrument
(Pharmacia Biosensor AB). IGF-I binding showed fast association and
slow non-first-order dissociation kinetics, and an equilibrium
Kd of 0.23 nM. IGF-II had similar
kinetics with slightly higher affinity. Analogues with mutations in the
first 3 amino acids of the B-region (des(, , ) IGF-I and long IGF-I)
showed 25 and 50 times lower affinity than IGF-I. Replacement of
residues 28-37 by Gly-Gly-Gly-Gly or deletion of residues 29-41 in
the C-region had little effect on the kinetic parameters, contrasting
with the markedly impaired binding of these analogues to the IGF-I
receptor. Swapping of the disulfide bridges in IGF-I and the C-region
mutants decreased the affinity dramatically for IGFBP-3, primarily by
decreasing the association rate. Insulin had approximately 1000 times
lower affinity than IGF-I.

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Copyright © 1996 by the American Society for Biochemistry and Molecular Biology.
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