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Two Insulin-Like Growth Factor (IGF)-Binding Proteins Are Responsible for the Selective Affinity for IGF-II of Cerebrospinal Fluid Binding Proteins^*

MONIREH ROGHANI, CLAUDINE LASSARRE, JÜRGEN ZAPF, GUILHERME POVOA and MICHEL BINOUX

Institut National de la Santé et de la Recherche Médicale, Unite de Recherches sur la Régulation de la Croissance, Hôpital Saint Antoine Paris, France
The Department of Medicine, University Hospital of Zurich Zurich, Switzerland
The Department of Endocrinology, Karolinska Hospital Stockholm, Sweden

Address all correspondence and requests for reprints to: Michel Binoux, INSERM U.142, Hopital Saint Antoine, 184 rue du Faubourg St. Antoine, 75571 Paris Cedex 12, France.

We have studied the relationships between the structure and affinity of two insulin-like growth factor-binding proteins (IGFBPs) purified from human cerebrospinal fluid (CSF). Competitive binding studies were performed using preparations of human recombinant IGF (rhIGF-I, rhIGF-II, and their labeled homologs) and the truncated variant form of IGFI, rh-Des-(l-3)-IGF-I. One of these BPs, which is the most consistently detected in CSF, corresponds to IGFBP-2. The other is a new form whose N-terminal sequence we reported earlier, which we call the 32–30K BP on the basis of its electrophoretic migration. Comparisons were made with an IGFBP-1 preparation purified from amniotic fluid and with two BPs purified from human serum, which are homologous to the CSF BPs.

The CSF BPs have particularly strong affinities for IGF-II. The estimated affinity constants (K_a) were 2 X 10¹⁰ M^–1 for IGFBP-2 and 10¹¹ M^–1 for the 32–30K BP. These affinities were 15–20 and 70 times stronger than the respective affinities for IGF-I. The affinity of the 32–30K BP is the strongest among the BPs identified to date. The two BPs isolated from serum, which correspond to the 32–30K CSF BP and IGFBP-2, had affinities for IGF-II and IGF-I similar to those of the CSF BPs. IGFBP-1 had nearly identical affinities for the two IGFs of approximately 10¹⁰ M^–1. Des-(l-3)-IGF-I failed to bind to the CSF BPs, but bound to IGFBP-1, although with a 40-fold weaker affinity than IGF-I.

From our data it would seem that IGFBP-1 has two classes of IGF-binding site, one of high and one of low (<10⁹ M^–1) affinity for both IGFs. The other two BPs, by contrast, each possess a predominant class of high affinity binding site for IGF-II. A second class of lower affinity (>10⁹ M^–1) sites bind both IGF-I and IGF-II. In the case of the 32-30K BP, these preferentially bind IGF-II; in the case of IGFBP-2, their binding of the two IGFs is similar. These different types of binding site may play an important role in controlling the bioavailability of IGF-I and IGF-II.

The predominance of the 32-30K BP and IGFBP-2 over the other molecular forms of BP in CSF and their selective affinity for IGF-II, the major IGF in this fluid, suggest that these two BPs have some specific role in the central nervous system.

^* This work was supported by the Institut National de la Sante et de la Recherche Medicale and Swiss National Science Foundation Grant 3046–087 (to J.Z.).

Recipient of a Nordisk grant for the study of growth.

Received June 5, 1990.

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