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Type: Journal article
Title: A Novel Approach to Identify Two Distinct Receptor Binding Surfaces of Insulin-like Growth Factor II
Author: Alvino, C.
McNeil, K.
Ong, S.
Delaine, C.
Booker, G.
Wallace, J.
Whittaker, J.
Forbes, B.
Citation: Journal of Biological Chemistry, 2009; 284(12):7653-7661
Publisher: Amer Soc Biochemistry Molecular Biology Inc
Issue Date: 2009
ISSN: 0021-9258
Statement of
Clair L. Alvino, Kerrie A. McNeil, Shee Chee Ong, Carlie Delaine, Grant W. Booker, John C. Wallace, Jonathan Whittaker, and Briony E. Forbes
Abstract: Very little is known about the residues important for the interaction of insulin-like growth factor II (IGF-II) with the type 1 IGF receptor (IGF-1R) and the insulin receptor (IR). Insulin, to which IGF-II is homologous, is proposed to cross-link opposite halves of the IR dimer through two receptor binding surfaces, site 1 and site 2. In the present study we have analyzed the contribution of IGF-II residues equivalent to insulin's two binding surfaces toward the interaction of IGF-II with the IGF-1R and IR. Four "site 1" and six "site 2" analogues were produced and analyzed in terms of IGF-1R and IR binding and activation. The results show that Val(43), Phe(28), and Val(14) (equivalent to site 1) are critical to IGF-1R and IR binding, whereas mutation to alanine of Gln(18) affects only IGF-1R and not IR binding. Alanine substitutions at Glu(12), Asp(15), Phe(19), Leu(53), and Glu(57) analogues resulted in significant (>2-fold) decreases in affinity for both the IGF-1R and IR. Furthermore, taking a novel approach using a monomeric, single-chain minimized IGF-1R we have defined a distinct second binding surface formed by Glu(12), Phe(19), Leu(53), and Glu(57) that potentially engages the IGF-1R at one or more of the FnIII domains.
Keywords: BALB 3T3 Cells
Receptor, IGF Type 1
Receptor, Insulin
Insulin-Like Growth Factor II
Peptide Mapping
Amino Acid Substitution
Binding Sites
Protein Structure, Tertiary
Protein Binding
Mutation, Missense
DOI: 10.1074/jbc.M808061200
Appears in Collections:Aurora harvest
Molecular and Biomedical Science publications

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