Complex with a Phage Display-Derived Peptide Provides Insight into the Function of Insulin-like Growth Factor I

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• 作者：Michelle L. Schaffer ; Kurt Deshayes ; Gerald Nakamura ; Sachdev Sidhu ; and Nicholas J. Skelton
• 刊名：Biochemistry
• 出版年：2003
• 出版时间：August 12, 2003
• 年：2003
• 卷：42
• 期：31
• 页码：9324 - 9334
• 全文大小：739K
• 年卷期：v.42,no.31(August 12, 2003)
• ISSN：1520-4995

文摘

The dramatic improvement in the NMR spectra of insulin-like growth factor I (IGF-I) in thepresence of a peptide identified from a phage display library has allowed for the first time the determinationof a high-resolution solution structure for much of IGF-I. The three helices of IGF-I in this complex havean arrangement similar to that seen in high-resolution crystal structures of IGF-I and insulin, althoughthere are differences in the conformation and precise location of helix 3. A cluster of hydrophobic andbasic side chains within the turn-helix motif of the peptide contact a hydrophobic patch on helices 1 and3 of IGF-I. The importance of this patch for tight binding was verified using alanine scanning mutagenesisof the peptide in two different phage display formats. Consistent with its antagonistic activity, the peptidebinds to a region implicated by mutagenesis studies to be important for association with IGF bindingproteins (IGFBPs). The ability of the peptide to also inhibit signaling has important implications for themanner in which IGF-I interacts with its receptor. Interestingly, the peptide uses the same binding site asdetergent and a fragment of IGFBP-5 identified in other IGF-I complexes. The ligand-induced structuralvariability of helix 3 in these complexes suggests that exchange between such conformations may be thesource of the dynamic nature of free IGF-I and likely has functional significance for the ability of IGF-Ito recognize two signaling receptors and six binding proteins with high affinity.