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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.

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