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A Central Domain Binding Site in Insulin-Like Growth Factor Binding Protein-5 for the Acid-Labile Subunit

Kolling Institute of Medical Research (S.M.T., R.C.B.), University of Sydney, Royal North Shore Hospital, St. Leonards, NSW 2065, Australia; Chiron Corporation (M.K.), Emeryville, California 94608; and Division of Endocrinology and Diabetology (J.Z.), Internal Medicine, University Hospital, Zurich, Switzerland

Address all correspondence and requests for reprints to: Robert C. Baxter, Ph.D., Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sidney, Department of Molecular Medicine, St. Leonards 2065, Australia.

Like insulin-like growth factor binding protein-3 (IGFBP-3), IGFBP-5 forms a ternary complex with insulin-like growth factor (IGF)-I or IGF-II, and the acid-labile subunit (ALS). The study of IGFBP-5/IGFBP-6 chimeric proteins with amino-terminal and middle domain swaps, has revealed the existence of a site in the middle domain of IGFBP-5, that binds to ALS in the absence of the IGFBP-5 carboxy-terminal domain. An IGFBP-6 chimeric protein containing the central domain of IGFBP-5 complexed efficiently with ALS, and a carboxy-terminally truncated IGFBP-5 mutant, IGFBP-5^1-169, also bound to ALS in the presence of IGFs, although with much less potency than full length rhIGFBP-5. In contrast to the latter, IGFBP-5^1-169 preferentially formed ternary complexes with IGF-II rather than IGF-I. These results indicate that a site which binds ALS exists in IGFBP-5 mutants which lack the IGFBP-5 carboxy-terminal domain.

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