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Mutagenesis of Basic Amino Acids in the Carboxyl-Terminal Region of Insulin-Like Growth Factor Binding Protein-5 Affects Acid-Labile Subunit Binding

Kolling Institute of Medical Research (S.M.F., R.C.B.), University of Sydney, Royal North Shore Hospital, St. Leonards, New South Wales 2065, Australia; and Division of Endocrinology (D.R.C.), Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7170

Address all correspondence and requests for reprints to: Sue M. Firth, Kolling Institute of Medical Research, Royal North Shore Hospital, St. Leonards 2065, Australia.

Like insulin-like growth factor binding protein-3 (IGFBP-3), IGFBP-5 was recently shown to form ternary complexes with insulin-like growth factor (IGF) and the acid-labile subunit (ALS). Previous studies using IGFBP-5/IGFBP-6 chimeric proteins have identified major and minor ALS binding sites in the carboxyl-terminal and central regions, respectively of IGFBP-5. We now report that ALS binds to IGFBP-3 (K_a = 1.1 ± 0.1 liters/nmol) and IGFBP-5 (K_a = 1.8 ± 0.5 liters/nmol) with similar binding affinities. Using site-specific mutants, we have identified residues K²¹¹/R²¹⁴/K²¹⁷/R²¹⁸ within the carboxyl-terminal region of IGFBP-5 as being essential for ALS binding. Mutation of K¹³⁴R¹³⁶ or K¹³⁸K¹³⁹ in the central region of IGFBP-5 resulted in a small decrease in ALS binding.

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