Characterization of the three 125I-iodination isomers of human insulin-like growth factor I (IGF1)

Schäffer, Lauge; Larsen, Ulla D.; Linde, Susanne; Hejnæs, Kim R.; Skriver, Lars

doi:10.1016/0167-4838(93)90084-5

Cited by 18 publications

(14 citation statements)

References 15 publications

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“…These residues form a continuous hydrophobic patch together with the aromatic sidechains of Phe 26 and Tyr 27 previously shown to be important for IR and IGF-1R binding (23). This hydrophobic cluster appears to provide the major contribution to the free energy of binding to both receptors; the corresponding residues are also important for the binding of both insulin to the IR and IGF-I to the IGF-1R.…”

Section: Discussionmentioning

confidence: 99%

A Novel Approach to Identify Two Distinct Receptor Binding Surfaces of Insulin-like Growth Factor II

Alvino

McNeil

Ong

et al. 2009

Journal of Biological Chemistry

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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. Insulin-like growth factor II (IGF-II)2 is a single-chain polypeptide with homology to IGF-I and insulin. Its 67 amino acids are arranged, like those counterparts in IGF-I, in four domains in the order B, C, A, and D from the N terminus ( The mitogenic and metabolic activities of the IGFs and insulin result from their interaction with the type 1 IGF receptor (IGF-1R) and/or the exon 11-(IR-A) and exon 11ϩ (IR-B) isoforms of the insulin receptor (IR). These class II receptor tyrosine kinases exist at the membrane as preformed disulfidelinked homodimers composed of two ␣ and two ␤ subunits in a ␤-␣-␣-␤ arrangement (reviewed in Refs. 9 -11). The IR and IGF-1R share between 41 and 84% sequence similarity that is most pronounced in their tyrosine kinase domains. Despite the homology in sequence and structure between these receptors, each exhibits distinct ligand binding preferences. The IGF-1R and IR bind their cognate ligands with high affinity (IGF-I and insulin, respectively). Both the IGF-1R and IR-A bind IGF-II with high affinity and are capable of mediating IGF-II action (12). Interestingly, the IR-B has a low affinity for IGF-II. The discerning factors for this isoform discrimination are largely undefined but may involve steric hindrance between the 12 amino acids encoded by exon 11 of IR-B and the IGF-II C domain.There are currently no structures of any of these ligand⅐receptor complexes. The binding of insulin to the IR is certainly the best characterized of these interactions. Insulin has two IR binding surfaces: the "site 1" binding surface lies within the insulin dimerization surface, whereas "site 2" overlaps its hexamer-forming surface. Insulin is proposed to crosslink opposite halves of the insulin receptor dimer through these two receptor binding surfaces (13,14). The stoichiometry of binding at physiological insulin concentrations is 1:1. However, each IR has two potential ligand binding pockets both also consisting of two ligand binding surfaces (site 1 and site 2 of one monomer and site 1Ј and site 2Ј of the other, which combine to give two identical binding pockets, site 1/2Ј and site 1Ј/2). This putative arrangement is consistent with the three-dimensional crystal structure of the IR ectodomain (15). Evidence from ligand binding studies suggests that insulin may cross-link only one pair of binding surfaces at a time, with binding of a second molecule to an unoccupied site acce...

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Section: Discussionmentioning

confidence: 99%

A Novel Approach to Identify Two Distinct Receptor Binding Surfaces of Insulin-like Growth Factor II

Alvino

McNeil

Ong

et al. 2009

Journal of Biological Chemistry

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“…Iodination has been used in this study as a structural and functional probe to investigate the interaction between bIGFBP-2 and its ligands IGF-I and IGF-II, at a molecular level. Previously, this approach has been successfully used to identify tyrosine residues of IGF-I which are important for association with the type-I IGF receptor (31,32) and tyrosine residues of both IGF-I and IGF-II which are important for association with bIGFBP-2 (9). The primary structure of bIGFBP-2 contains six tyrosine residues.…”

Section: Discussionmentioning

confidence: 99%

The Insulin-like Growth Factor (IGF) Binding Site of Bovine Insulin-like Growth Factor Binding Protein-2 (bIGFBP-2) Probed by Iodination

Hobba

Forbes

Parkinson

et al. 1996

Journal of Biological Chemistry

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“…AE extraction can be improved by subsequent cryoprecipitation, and by the use of truncated IGF-I (des(1-3) IGF-I) with reduced IGFBP affinity as the radioligand [8]. Furthermore, the use of monoiodinated radioligands [9,10] [11]. Alternatively, antibodies specific for IGF-I (with no crossreactivity with IGF-II) have been developed, and so the addition of excess IGF-II can saturate the IGFBPs, eliminating the need for acidic IGFBP extraction [12].…”

Section: Determination Of Igf-imentioning

confidence: 99%

Determination of Insulin-Like Growth Factor I in Children: Normal Values and Clinical Use

Juul

2001

Horm Res Paediatr

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Circulating insulin-like growth factor I (IGF-I) levels are stable throughout the day and correlate with pulsatile endogenous growth hormone (GH) secretion. A single measurement of IGF-I may, therefore, provide information on the GH secretory status of an individual. The clinical use of IGF-I determination in the evaluation of short stature in children suspected of GH deficiency will be discussed. Previous methodological problems have now mostly been overcome, and IGF-I can be determined in serum from healthy children, although concentrations exhibit large inter-individual variations relating to age, gender and pubertal maturation. These variations must be taken into account before IGF-I can be evaluated in a clinical situation, and before it can be stated whether a certain value is too low for a given age. The diagnostic sensitivities of IGF-I reported in relation to the outcome of GH provocative testing are variable (47–100%). This variability probably results from the use of different IGF-I assays, IGF-I reference ranges, and different GH testing procedures. When proper IGF-I assays and reference ranges are used, however, IGF-I determination results in valid diagnostic information regarding children exhibiting short stature. Thus, an IGF-I value should always be evaluated together with auxological information and GH testing results before a decision is taken on whether or not to start GH therapy.

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Characterization of the three 125I-iodination isomers of human insulin-like growth factor I (IGF1)

Cited by 18 publications

References 15 publications

A Novel Approach to Identify Two Distinct Receptor Binding Surfaces of Insulin-like Growth Factor II

A Novel Approach to Identify Two Distinct Receptor Binding Surfaces of Insulin-like Growth Factor II

The Insulin-like Growth Factor (IGF) Binding Site of Bovine Insulin-like Growth Factor Binding Protein-2 (bIGFBP-2) Probed by Iodination

Determination of Insulin-Like Growth Factor I in Children: Normal Values and Clinical Use

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