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Type: Journal article
Title: Structural basis for the lower affinity of the insulin-like growth factors for the insulin receptor
Author: Gauguin, L.
Klaproth, B.
Sajid, W.
Andersen, A.
McNeil, K.
Forbes, B.
De Meyts, P.
Citation: Journal of Biological Chemistry, 2008; 283(5):2604-2613
Publisher: Amer Soc Biochemistry Molecular Biology Inc
Issue Date: 2008
ISSN: 0021-9258
Statement of
Lisbeth Gauguin, Birgit Klaproth, Waseem Sajid, Asser S. Andersen, Kerrie A. McNeil, Briony E. Forbes and Pierre De Meyts
Abstract: Insulin and the insulin-like growth factors (IGFs) bind with high affinity to their cognate receptor and with lower affinity to the noncognate receptor. The major structural difference between insulin and the IGFs is that the IGFs are single chain polypeptides containing A-, B-, C-, and D-domains, whereas the insulin molecule contains separate A- and B-chains. The C-domain of IGF-I is critical for high affinity binding to the insulin-like growth factor I receptor, and lack of a C-domain largely explains the low affinity of insulin for the insulin-like growth factor I receptor. It is less clear why the IGFs have lower affinity for the insulin receptor. In this study, 24 insulin analogues and four IGF analogues were expressed and analyzed to explore the role of amino acid differences in the A- and B-domains between insulin and the IGFs in binding affinity for the insulin receptor. Using the information obtained from single substituted analogues, four multiple substituted analogues were produced. A "quadruple insulin" analogue ([Phe(A8), Ser(A10), Thr(B5), Gln(B16)]Ins) showed affinity as IGF-I for the insulin receptor, and a "sextuple insulin" analogue ([Phe(A8), Ser(A10), Thr(A18), Thr(B5), Thr(B14), Gln(B16)]Ins) showed an affinity close to that of IGF-II for the insulin receptor, whereas a "quadruple IGF-I" analogue ([His(4), Tyr(15), Thr(49), Ile(51)]IGF-I) and a "sextuple IGF-II" analogue ([His(7), Ala(16), Tyr(18), Thr(48), Ile(50), Asn(58)]IGF-II) showed affinities similar to that of insulin for the insulin receptor. The mitogenic potency of these analogues correlated well with the binding properties. Thus, a small number of A- and B-domain substitutions that map to the IGF surface equivalent to the classical binding surface of insulin weaken two hotspots that bind to the insulin receptor site 1.
Keywords: Cell Line
Receptor, Insulin
Insulin-Like Growth Factor I
Insulin-Like Growth Factor II
Protein Precursors
Amino Acid Substitution
Binding, Competitive
Amino Acid Sequence
Protein Structure, Tertiary
Sequence Homology, Amino Acid
Models, Molecular
Molecular Sequence Data
In Vitro Techniques
DOI: 10.1074/jbc.M709220200
Appears in Collections:Aurora harvest
Molecular and Biomedical Science publications

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